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1
Dang, Ying, Xiaojun Wang, Walter J. Esselman, and Yong-Hui Zheng. "Identification of APOBEC3DE as Another Antiretroviral Factor from the Human APOBEC Family." Journal of Virology 80, no. 21 (August 18, 2006): 10522–33. http://dx.doi.org/10.1128/jvi.01123-06.
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ABSTRACT A tandem arrayed gene cluster encoding seven cytidine deaminase genes is present on human chromosome 22. These are APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3DE, APOBEC3F, APOBEC3G, and APOBEC3H. Three of them, APOBEC3G, APOBEC3F, and APOBEC3B, block replication of human immunodeficiency virus type 1 (HIV-1) and many other retroviruses. In addition, APOBEC3A and APOBEC3C block intracellular retrotransposons and simian immunodeficiency virus (SIV), respectively. In opposition to APOBEC genes, HIV-1 and SIV contain a virion infectivity factor (Vif) that targets APOBEC3F and APOBEC3G for polyubiquitylation and proteasomal degradation. Herein, we studied the antiretroviral activities of the human APOBEC3DE and APOBEC3H. We found that only APOBEC3DE had antiretroviral activity for HIV-1 or SIV and that Vif suppressed this antiviral activity. APOBEC3DE was encapsidated and capable of deaminating cytosines to uracils on viral minus-strand DNA, resulting in disruption of the viral life cycle. Other than GG-to-AG and AG-to-AA mutations, it had a novel target site specificity, resulting in introduction of GC-to-AC mutations on viral plus-strand DNA. Such mutations have been detected previously in HIV-1 clinical isolates. In addition, APOBEC3DE was expressed much more extensively than APOBEC3F in various human tissues and it formed heteromultimers with APOBEC3F or APOBEC3G in the cell. From these studies, we concluded that APOBEC3DE is a new contributor to the intracellular defense network, resulting in suppression of retroviral invasion.
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Chu, Charles C., Stefano Vergani, Xiao-Jie Yan, Arvind Dhayalan, Piers E. M. Patten, Thomas MacCarthy, Chaohui Yuan, et al. "APOBEC gene family expression and hallmarks in chronic lymphocytic leukemia." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 76.16. http://dx.doi.org/10.4049/jimmunol.198.supp.76.16.
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Abstract The hallmark activity of APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) family of cytidine deaminases, including activation-induced deaminase (AID) and APOBEC3 genes, has been detected in somatic mutation signatures by ultra-deep sequencing of the genomes of many cancers, including chronic lymphocytic leukemia (CLL). The acquisition of these mutations is hypothesized to lead to the progression towards aggressive disease in cancer. To examine this in CLL, we tested if increased APOBEC family member gene expression in CLL cells, as measured by microarray and quantitative real time PCR, correlated with worse patient outcome. Higher levels of AID, APOBEC3B, APOBEC3F and APOBEC3H in CLL cells correlated with worse patient outcome, whereas APOBEC3G did not. Interestingly, higher levels of a truncated splice variant of APOBEC3F tended to correlate with better patient outcome. The expression of truncated APOBEC3F may possibly interfere with APOBEC family member mutation activity. To test mutation activity, CLL cells were activated by transfer into NOD-scid IL2Rγnull mice, a xenograft model of human CLL, and hallmark mutation signatures in the expressed immunoglobulin variable region (IGHV) of CLL cells were analyzed by targeted ultra-deep sequencing. Induced IGHV mutation hallmarks consistent with AID were found. These data support the hypothesis that expression and mutation activity of APOBEC family members, such as AID, in CLL cells could lead to adverse patient consequences.
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Caswell, Deborah, and Charles Swanton. "Distinct Mutagenic Activity of APOBEC3G Cytidine Deaminase Identified in Bladder Cancer." Cancer Research 83, no. 4 (February 15, 2023): 487–88. http://dx.doi.org/10.1158/0008-5472.can-22-3598.
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Abstract The APOBEC cytidine deaminase enzyme family is linked to mutational signatures identified in cancer. While previous work has provided insights into the role of APOBEC3A and APOBEC3B in mutational processes in cancer, understanding of the mutational signatures induced by other APOBEC family members is limited. In this issue of Cancer Research, Liu and colleagues investigated the role of APOBEC3G (A3G) in bladder cancer. The authors revealed that transgenic expression of A3G in a murine bladder cancer model promotes tumorigenesis and induces a unique mutational signature distinct from previously identified APOBEC signatures. Expression of this A3G-related mutational signature correlated with significantly worse survival in patients with urothelial bladder carcinoma, and A3G expression was identified in 21 different cancer types. These findings suggest that different APOBEC3 enzymes induce unique mutation signatures and play distinct roles in cancer evolution. More complete understanding of the function of each APOBEC3 enzyme will improve anticancer therapy. See related article by Liu et al., p. 506
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Chu, Charles C., Xiao-Jie Yan, Arvind Dhayalan, Piers E. Patten, Thomas MacCarthy, Chaohui Yuan, Jacqueline C. Barrientos, et al. "The Correlation of APOBEC Gene Family Member Expression with Worse CLL Patient Outcome Suggests a Role in CLL Mutational Evolution." Blood 126, no. 23 (December 3, 2015): 363. http://dx.doi.org/10.1182/blood.v126.23.363.363.
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Abstract A mutational signature consistent with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) activity has been identified in somatic mutations found in large-scale surveys of ultra-deep sequencing data from many human cancers including chronic lymphocytic leukemia (CLL). APOBEC is a cytidine deaminase family made up of eleven genes, including AID (activation-induced cytidine deaminase) and APOBEC3B, both of which have been implicated in somatic mutation in various cancers, including CLL. These observations have led to the hypothesis that APOBEC cytidine deaminases may be driving somatic mutations leading to the development of more aggressive cancers. Therefore, we examined APOBEC gene family member RNA expression levels in CLL to test for correlations with expression levels and patient outcome. We further examined if CLL cells generated de novo APOBEC family member mutational patterns in the immunoglobulin variable region gene (IGHV) after implantation in a mouse xenograft model of CLL. CLL peripheral blood mononuclear cells (PBMCs) and associated clinical data were collected from patients after informed consent as approved by the Institutional Review Board at the North Shore-Long Island Jewish Health System and in accordance with the Helsinki Declaration. CLL samples were chosen based on availability with no pre-established inclusion/exclusion criteria. CLL RNA expression levels were examined by microarray or quantitative real-time PCR (qPCR). For microarray studies, CLL B cells were purified prior to RNA isolation and acquisition of microarray expression data using Illumina Human WG6 and HT12 bead chips, followed by quantile normalization using GenomeStudio software (Illumina). For qPCR, RNA expression from CLL PBMCs was measured relative to glyceraldehyde 3-phosphate dehydrogenase gene expression by Taqman assay with Roche UPL probes and LightCycler 480. To examine de novo mutations in CLL, the IGHV region was ultra-deep sequenced (Roche 454 FLX system) from human CLL cells recovered from the NOD/Shi-scid,γcnull (NSG) xenograft mouse model of CLL as approved by the Institutional Animal Care and Use Committee at the North Shore-Long Island Jewish Health System. CLL patient (N = 65) RNA expression by microarray showed very low levels of APOBEC1, 2, 3A, 3B, 3D, 4, and AID, modest levels of APOBEC3C and 3H, and high levels of APOBEC3F and 3G. Higher AID expression levels significantly correlated (P <0.05) with shorter time to first treatment (TFT), which was anticipated based on previous reports. Interestingly APOBEC3B and APOBEC3F expression differences showed possible trends correlating with worse patient outcome. Therefore, we tested select APOBEC gene family members by qPCR. For qPCR, we utilized the CLL patient cohort (N= 83) previously found to indicate that AID expression was a risk factor for worse patient outcome in a multivariate analysis (Patten et al. 2012 Blood 120:4802). RNA expression by qPCR followed the same pattern as the microarray data: AID and APOBEC3B had very low levels, APOBEC3H had modest levels, and APOBEC3F and 3G had high levels. Similar to AID, patients could be grouped based on the presence or absence of detectable APOBEC3B, with its presence showing a significant correlation (P <0.05) with worse TFT and overall survival. Higher levels of APOBEC3F and 3H showed a trend towards a correlation with shorter TFT, while differences in APOBEC3G expression had no significant correlation with patient outcome. Thus, not only did we confirm the correlation of AID expression with worse patient outcome, but we also found APOBEC3B and potentially APOBEC3F and 3H correlate with worse patient outcome. To test if CLL cells can acquire de novo mutations indicative of APOBEC gene family member activity, human CLL cells were transferred into NSG mice. After CLL cells proliferated for 4-14 weeks in this xenograft model, the IGHV region was amplified, ultra-deep sequenced, and analyzed for specific mutational characteristics of various APOBEC gene family members. The results of these ongoing analyses will be presented. In conclusion, the expression levels of the APOBEC gene family members AID, APOBEC3B, and potentially APOBEC3F and 3H, correlate with worse patient outcome. These data are consistent with the hypothesis that APOBEC gene family member activity may promote new mutations at sites outside the IG gene loci leading to the evolution of aggressive CLL. Disclosures Barrientos: Pharmacyclics, Celgene, and Genentech: Membership on an entity's Board of Directors or advisory committees; Gilead, Pharmacyclics, and AbbVie: Research Funding.
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Mikl, Marie C., Ian N. Watt, Mason Lu, Wolf Reik, Sarah L. Davies, Michael S. Neuberger, and Cristina Rada. "Mice Deficient in APOBEC2 and APOBEC3." Molecular and Cellular Biology 25, no. 16 (August 15, 2005): 7270–77. http://dx.doi.org/10.1128/mcb.25.16.7270-7277.2005.
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ABSTRACT The activation-induced deaminase/apolipoprotein B-editing catalytic subunit 1 (AID/APOBEC) family comprises four groups of proteins. Both AID, a lymphoid-specific DNA deaminase that triggers antibody diversification, and APOBEC2 (function unknown) are found in all vertebrates examined. In contrast, APOBEC1, an RNA-editing enzyme in gastrointestinal cells, and APOBEC3 are restricted to mammals. The function of most APOBEC3s, of which there are seven in human but one in mouse, is unknown, although several human APOBEC3s act as host restriction factors that deaminate human immunodeficiency virus type 1 replication intermediates. A more primitive function of APOBEC3s in protecting against the transposition of endogenous retroelements has, however, been proposed. Here, we focus on mouse APOBEC2 (a muscle-specific protein for which we find no evidence of a deaminating activity on cytidine whether as a free nucleotide or in DNA) and mouse APOBEC3 (a DNA deaminase which we find widely expressed but most abundant in lymphoid tissue). Gene-targeting experiments reveal that both APOBEC2 (despite being an ancestral member of the family with no obvious redundancy in muscle) and APOBEC3 (despite its proposed role in restricting endogenous retrotransposition) are inessential for mouse development, survival, or fertility.
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Harris, Reuben S., Matthew C. Jarvis, Michael A. Carpenter, Margaret R. Brown, Prokopios P. Argyris, William Brown, and Douglas Yee. "Abstract P5-12-01: Apobec mutation signature in breast cancer explained by combinatorial action of apobec3a and apobec3b." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–12–01—P5–12–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-12-01.
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Abstract Background: Mutations drive the initiation and progression of cancer. A leading druggable source of mutation in cancer is enzymatic deamination of single-stranded DNA cytosines by cellular APOBEC3 enzymes. Cytosine-to-uracil deamination can result in a variety of different mutational outcomes including DNA breakage and chromosomal aberrations as well as single base substitution mutations. The latter are comprised of C-to-T and C-to-G mutations in TCA or TCT trinucleotides and attributable to the intrinsic preference of several APOBEC3 family members for binding to these motifs. This mutation pattern, commonly called the “APOBEC signature”, is evident in approximately one-quarter of primary breast tumors and one-third of metastatic breast tumors. Although multiple APOBEC3 enzymes have been implicated as a source of this signature in breast cancer (namely, APOBEC3A, APOBEC3B, and APOBEC3H), the literature is full of conflicting views and it is not clear which of these enzymes contributes most significantly to the mutational landscape of breast cancer. Methods: The near-haploid human cell line, HAP1, was engineered to express the HSV-1 TK gene as a mutation reporter. Candidate APOBEC3 enzymes were expressed individually and confirmed by immunoblotting and activity assays. DNA breakage was measured directly by COMET assays and DNA damage responses indirectly by phosphorylated gamma-H2AX staining. Mutation frequencies were quantified by assaying rates of drug resistance, and mutation patterns were analyzed by sequencing locally in TK and globally across whole genomes. Results: APOBEC3A and APOBEC3B both caused significant increases in chromosomal DNA breakage and DNA damage responses. These enzymes also elevated drug resistance mutation frequencies. In contrast, expression of active APOBEC3H or catalytic mutant derivatives of APOBEC3A and APOBEC3B failed to trigger increases beyond normal spontaneous levels. Interestingly, APOBEC3A and APOBEC3B both inflicted mutation signatures that were indistinguishable locally in TK and globally across whole genomes. The vast majority of these APOBEC signature mutations were dispersed (non-kataegic) and not associated with obvious mesoscale chromosomal features such as single-stranded loop regions of stem-loop structures. Computational comparisons of the broader pentanucleotide APOBEC3A and APOBEC3B mutation signatures and those extracted from 794 primary breast tumor genomes (ICGC cohort) revealed an APOBEC3A-biased subset, an APOBEC3B-biased subset, and a larger group of tumors best explained by combinatorial action of both of these enzymes. Conclusions: Our results indicate that APOBEC3A and APOBEC3B contribute combinatorially in most instances to the observed APOBEC mutation signature in breast cancer. These results provide a framework for developing diagnostic and therapeutic approaches for APOBEC-positive breast cancer. Citation Format: Reuben S Harris, Matthew C Jarvis, Michael A Carpenter, Margaret R Brown, Prokopios P Argyris, William Brown, Douglas Yee. Apobec mutation signature in breast cancer explained by combinatorial action of apobec3a and apobec3b [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-12-01.
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Talluri, Srikanth, Mehmet Kemal Samur, Jialan Shi, Rao Prabhala, Hervé Avet-Loiseau, Masood A. Shammas, and Nikhil Munshi. "Critical Role for Apobec and Its Interacting Partners in Mediating Mutations and Cell Growth in Multiple Myeloma (MM)." Blood 132, Supplement 1 (November 29, 2018): 4462. http://dx.doi.org/10.1182/blood-2018-99-118441.
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Abstract The APOBEC family of cytidine deaminases include AID (activity induced deaminase) and 10 related APOBEC enzymes (A1,A2,A3A,A3B,A3C,A3D,A3F,A3G,A3H and A4). AID is well studied for its role in somatic hyper mutation and class switch recombination of immunoglobulin genes. APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) have been shown to have roles in mRNA editing and in antiviral immunity. Recently, a causal role for the AID/APOBECs in inducing somatic mutations in myeloma has been proposed and we have previously published that APOBEC signature mutations as a frequent event in Myeloma. We have also observed that APOBEC-mediated mutations may account for mutations associated with progression of smoldering myeloma to MM. We further investigated the role of APOBEC in genomic changes in MM and observed that APOBEC expression and activity is elevated in myeloma cell lines as well as patient samples. Using knockdown and over expression approaches, we showed that depletion of APOBECs in myeloma cell lines reduces genomic instability. Following APOBEC3G knock down we observed decreased DNA damage (by g-H2AX), decrease in acquisition of new copy number events over time, and reduced mutational load, strongly suggesting that inhibiting APOBECs could be a potential approach to reduce genome evolution in MM. We next investigated the effect of APOBEC inhibition on myeloma cell proliferation. We observed that Sh-RNA-based APOBEC knock down in MM1S and H929 MM cell lines, led to significant inhibition of MM cell proliferation, and induction of apoptotic cell death. Associated with APOBEC knockdown, we also observed increased levels of Cyclin-dependent kinase inhibitor 1B (p27Kip1) at both RNA and protein level. By immunoprecipitation we found that APOBEC3G interacts and inhibits the RNA binding protein DEAD-END 1 (DND1), thereby preventing it from inhibiting miR-221-mediated targeting of p27 transcripts. Knockdown of DND1, or over-expression of miR-221 in APOBEC-depleted cells rescued the cell proliferation defects with concomitant decrease in p27 levels. These results show that APOBCs bind to and sequester DND1, leading to miR-221-mediated depletion of p27. In the absence of APOBEC, DND1 prevents the degradation of p27 mRNA, leading to elevated p27 levels and inhibition of cell cycle, suggesting a role for APOBECs in regulating MM cell proliferation that might be independent of its RNA/DNA mutator function. Taken together, these results indicate a significant functional role for APOBECs both in genome evolution as well as cell growth in myeloma and may constitute an important therapeutic target. Disclosures Munshi: OncoPep: Other: Board of director.
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Talluri, Srikanth, Mehmet Kemal Samur, Leutz Buon, Stekla A. Megan, Purushothama Nanjappa, Rao Prabhala, Masood A. Shammas, and Nikhil C. Munshi. "Dysregulated Aid/Apobec Family Proteins Promote Genomic Instability in Multiple Myeloma." Blood 128, no. 22 (December 2, 2016): 803. http://dx.doi.org/10.1182/blood.v128.22.803.803.
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Abstract The AID/APOBEC family of cytidine deaminase proteins includes AID (activity induced deaminase), and 10 related APOBEC enzymes (A1, A2, A3A, A3B, A3C, A3D, A3F, A3G, A3H and A4). AID has been well-studied for its role in somatic hyper mutation and class switch recombination of immunoglobulin genes whereas APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) have been shown to have roles in mRNA editing and in antiviral immunity. Dysregulated activity of APOBECs causes C >T transitions or C>G, C>A transversions in DNA. We have recently shown APOBEC signature mutation pattern in multiple myeloma (MM) genomes (Bolli et al Nat. Comm. 2014), and interestingly, the APOBEC mutation signature correlates with sub clonal diversity in myeloma. A role for the AID/APOBECs in generation of somatic mutations has also been proposed in a variety of other cancers based on identification of APOBEC signature mutations In order to understand which APOBECs are dysregulated in myeloma, we performed RNA sequencing analysis of primary myeloma cells from 409 newly-diagnosed MM patients and myeloma cell lines. Our analysis showed elevated expression of several APOBEC family members; mainly A3A, A3B, A3C, and A3G. We then optimized a plasmid-based functional assay and found high cytidine deaminase activity in extracts from a number of myeloma cell lines and patient derived CD138+ cells compared to CD138+ cells from healthy donors, suggesting that APOBECs are dysregulated in myeloma. We then investigated the impact of elevated APOBEC expression/function on overall genome maintenance and acquisition of genomic changes (such as amplifications, deletions) overtime. We used shRNA-mediated knockdown of specific APOBEC proteins in myeloma cell lines and investigated the acquisition of genomic changes in control and knockdown cells during their growth in culture, using SNP (Single Nucleotide Polymorphism) arrays and WGS (whole genome sequencing) platforms. Our results with both approaches showed significant reduction in the accumulation of copy number changes (both amplifications and deletions) and overall mutation load after APOBEC knockdown. Evaluation with both the SNP and WGS showed that when control and APOBEC knockdown cells were cultured for three weeks, the acquisition of new copy number and mutational changes throughout genome were reduced by ~50%. We next investigated the relationship between APOBEC expression/activity in MM and other DNA repair pathways. Using an in vitro HR activity assay, we measured HR activity in extracts from control and APOBEC knockdown cells. Depletion of APOBEC proteins resulted in 50-80% reduction in in vitro HR activity of the extracts. We also evaluated correlation between HR activity and gene expression using RNA-seq data from myeloma cells derived from 100 patients at diagnosis and identified the genes whose expression correlated with HR activity. Elevated expression of APOBECs 3D, 3G and 3F significantly correlated with high HR activity (R=0.3; P≤0.02), suggesting their relevance to HR. Analyzing genomic copy number information for each patient we have also observed significant correlation between higher expression of A3G and increased genomic instability in this dataset (P=0.0045). In summary, our study shows that dysregulated APOBECs induce mutations and genomic instability, and inhibiting APOBEC activity could reduce the rate of accumulation of ongoing genomic changes. This data sheds light on biology of the disease as well as clonal evolution. Disclosures Munshi: Amgen: Consultancy; Oncopep: Patents & Royalties; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Merck: Consultancy; Pfizer: Consultancy.
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Köck, Josef, and Hubert E. Blum. "Hypermutation of hepatitis B virus genomes by APOBEC3G, APOBEC3C and APOBEC3H." Journal of General Virology 89, no. 5 (May 1, 2008): 1184–91. http://dx.doi.org/10.1099/vir.0.83507-0.
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Hepatitis B virus (HBV) is a DNA virus that causes liver disease and replicates by reverse transcription of an RNA template. Previous studies have reported that HBV genomes bearing G→A hypermutation are present at low frequency in human serum. These mutations are most likely due to the activity of apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC) cytosine deaminases, cellular proteins known to confer innate immunity against retroviruses by generating lethal hypermutations in viral genomes. This study assessed APOBEC3G, APOBEC3C and APOBEC3H, three members of this protein family present in human liver, for their ability to edit HBV genomes. Transfection of human HepG2 hepatoma cells with a plasmid encoding the APOBEC3C protein resulted in abundant G→A mutations in the majority of newly formed HBV genomes. By contrast, transfection of APOBEC3G- and APOBEC3H-encoding plasmids only marginally increased hypermutation rates above the level caused by the cytosine deaminases naturally present in HepG2 cells. APOBEC3G- and APOBEC3H-mediated hypermutation, however, was clearly revealed by transfection of chicken LMH hepatoma cells, which lack endogenous cytosine deaminases. These results indicate that APOBEC3G, APOBEC3C and APOBEC3H have the ability to edit HBV DNA and that each protein is likely to contribute to various degrees to the generation of modified genomes in human liver cells.
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Granadillo Rodríguez, Milaid, Ben Flath, and Linda Chelico. "The interesting relationship between APOBEC3 deoxycytidine deaminases and cancer: a long road ahead." Open Biology 10, no. 12 (December 2020): 200188. http://dx.doi.org/10.1098/rsob.200188.
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Cancer is considered a group of diseases characterized by uncontrolled growth and spread of abnormal cells and is propelled by somatic mutations. Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) family of enzymes are endogenous sources of somatic mutations found in multiple human cancers. While these enzymes normally act as an intrinsic immune defence against viruses, they can also catalyse ‘off-target’ cytidine deamination in genomic single-stranded DNA intermediates. The deamination of cytosine forms uracil, which is promutagenic in DNA. Key factors to trigger the APOBEC ‘off-target’ activity are overexpression in a non-normal cell type, nuclear localization and replication stress. The resulting uracil-induced mutations contribute to genomic variation, which may result in neutral, beneficial or harmful consequences for the cancer. This review summarizes the functional and biochemical basis of the APOBEC3 enzyme activity and highlights their relationship with the most well-studied cancers in this particular context such as breast, lung, bladder, and human papillomavirus-associated cancers. We focus on APOBEC3A, APOBEC3B and APOBEC3H haplotype I because they are the leading candidates as sources of somatic mutations in these and other cancers. Also, we discuss the prognostic value of the APOBEC3 expression in drug resistance and response to therapies.
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Xu, Wendy Kaichun, Hyewon Byun, and Jaquelin P. Dudley. "The Role of APOBECs in Viral Replication." Microorganisms 8, no. 12 (November 30, 2020): 1899. http://dx.doi.org/10.3390/microorganisms8121899.
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Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) proteins are a diverse and evolutionarily conserved family of cytidine deaminases that provide a variety of functions from tissue-specific gene expression and immunoglobulin diversity to control of viruses and retrotransposons. APOBEC family expansion has been documented among mammalian species, suggesting a powerful selection for their activity. Enzymes with a duplicated zinc-binding domain often have catalytically active and inactive domains, yet both have antiviral function. Although APOBEC antiviral function was discovered through hypermutation of HIV-1 genomes lacking an active Vif protein, much evidence indicates that APOBECs also inhibit virus replication through mechanisms other than mutagenesis. Multiple steps of the viral replication cycle may be affected, although nucleic acid replication is a primary target. Packaging of APOBECs into virions was first noted with HIV-1, yet is not a prerequisite for viral inhibition. APOBEC antagonism may occur in viral producer and recipient cells. Signatures of APOBEC activity include G-to-A and C-to-T mutations in a particular sequence context. The importance of APOBEC activity for viral inhibition is reflected in the identification of numerous viral factors, including HIV-1 Vif, which are dedicated to antagonism of these deaminases. Such viral antagonists often are only partially successful, leading to APOBEC selection for viral variants that enhance replication or avoid immune elimination.
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Liu, Qin, Yue-wen Luo, Ruo-yan Cao, Xue Pan, Xi-juan Chen, Si-yuan Zhang, Wei-lin Zhang, Jia-ying Zhou, Bin Cheng, and Xian-yue Ren. "Association between APOBEC3H-Mediated Demethylation and Immune Landscape in Head and Neck Squamous Carcinoma." BioMed Research International 2020 (July 25, 2020): 1–17. http://dx.doi.org/10.1155/2020/4612375.
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Immunotherapy has been demonstrated as a promising strategy in controlling head and neck squamous cell carcinoma (HNSC). The AID/APOBEC family is well characterized as DNA mutator and considered to play critical roles in immune responses in HNSC. However, the expression pattern and deamination-dependent demethylation roles of AID/APOBECs in HNSC are unclear. In this study, the RNA-seq and DNA methylation profiles of HNSC from TCGA database and cell-based experiments were applied to analyze the relationships between AID/APOBEC expression levels, patients’ clinical outcomes, methylation alterations, and immune responses. Here, we found that APOBEC3H was abnormally upregulated in HNSC patients. HPV+ patients tended to have higher APOBEC3H levels than HPV- patients. Remarkably, patients with high APOBEC3H levels showed a favorable overall survival. Furthermore, tumors with high APOBEC3H levels exhibited a genome-wide DNA hypomethylation pattern. APOBEC3H was identified to demethylate and upregulate CXCL10 and improve CD8+ T cell tumor infiltration in the tumor microenvironment. Collectively, APOBEC3H plays critical roles in CD8+ T cell immune infiltration and activation in HNSC, which may be a potential biomarker for oncoimmunotherapy in HNSC.
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Cheng, Adam Z., Sofia N. Moraes, Nadine M. Shaban, Elisa Fanunza, Craig J. Bierle, Peter J. Southern, Wade A. Bresnahan, Stephen A. Rice, and Reuben S. Harris. "APOBECs and Herpesviruses." Viruses 13, no. 3 (February 28, 2021): 390. http://dx.doi.org/10.3390/v13030390.
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The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved strategies to escape restriction by the APOBEC enzymes of their hosts. HIV-1 and related retroviruses are thought to be the predominant natural substrates of APOBEC enzymes due to obligate single-stranded (ss)DNA replication intermediates, abundant evidence for cDNA strand C-to-U editing (genomic strand G-to-A hypermutation), and a potent APOBEC degradation mechanism. In contrast, much lower mutation rates are observed in double-stranded DNA herpesviruses and the evidence for APOBEC mutation has been less compelling. However, recent work has revealed that Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and herpes simplex virus-1 (HSV-1) are potential substrates for cellular APOBEC enzymes. To prevent APOBEC-mediated restriction these viruses have repurposed their ribonucleotide reductase (RNR) large subunits to directly bind, inhibit, and relocalize at least two distinct APOBEC enzymes—APOBEC3B and APOBEC3A. The importance of this interaction is evidenced by genetic inactivation of the EBV RNR (BORF2), which results in lower viral infectivity and higher levels of C/G-to-T/A hypermutation. This RNR-mediated mechanism therefore likely functions to protect lytic phase viral DNA replication intermediates from APOBEC-catalyzed DNA C-to-U deamination. The RNR-APOBEC interaction defines a new pathogen-host conflict that the virus must win in real-time for transmission and pathogenesis. However, partial losses over evolutionary time may also benefit the virus by providing mutational fuel for adaptation.
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Guo, Honghong, Ling Zhu, Lu Huang, Zhen Sun, Hui Zhang, Baoting Nong, and Yuanyan Xiong. "APOBEC Alteration Contributes to Tumor Growth and Immune Escape in Pan-Cancer." Cancers 14, no. 12 (June 8, 2022): 2827. http://dx.doi.org/10.3390/cancers14122827.
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The accumulating evidence demonstrates that the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. In particular, the APOBEC3 family was shown to induce tumor mutations by an aberrant DNA editing mechanism. However, knowledge regarding the reconstitution of the APOBEC family genes across cancer types is still lacking. Here, we systematically analyzed the molecular alterations, immuno-oncological features, and clinical relevance of the APOBEC family in pan-cancer. We found that APOBEC genes were widely and significantly differentially expressed between normal and cancer samples in 16 cancer types, and that their expression levels are significantly correlated with the prognostic value in 17 cancer types. Moreover, two patterns of APOBEC-mediated stratification with distinct immune characteristics were identified in different cancer types, respectively. In ACC, for example, the first pattern of APOBEC-mediated stratification was closely correlated with the phenotype of immune activation, which was characterized by a high immune score, increased infiltration of CD8 T cells, and higher survival. The other pattern of APOBEC-mediated stratification was closely correlated with the low-infiltration immune phenotype, which was characterized by a low immune score, lack of effective immune infiltration, and poorer survival. Further, we found the APOBEC-mediated pattern with low-infiltration immune was also highly associated with the advanced tumor subtype and the CIMP-high tumor subtype (CpG island hypermethylation). Patients with the APOBEC-mediated pattern with immune activation were more likely to have therapeutic advantages in ICB (immunological checkpoint blockade) treatment. Overall, our results provide a valuable resource that will be useful in guiding oncologic and therapeutic analyses of the role of APOBEC family in cancer.
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Delebecque, Frédéric, Rodolphe Suspène, Sara Calattini, Nicoletta Casartelli, Ali Saïb, Alain Froment, Simon Wain-Hobson, Antoine Gessain, Jean-Pierre Vartanian, and Olivier Schwartz. "Restriction of Foamy Viruses by APOBEC Cytidine Deaminases." Journal of Virology 80, no. 2 (January 15, 2006): 605–14. http://dx.doi.org/10.1128/jvi.80.2.605-614.2006.
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ABSTRACT Foamy viruses (FVs) are nonpathogenic retroviruses infecting many species of mammals, notably primates, cattle, and cats. We have examined whether members of the apolipoprotein B-editing catalytic polypeptide-like subunit (APOBEC) family of antiviral cytidine deaminases restrict replication of simian FV. We show that human APOBEC3G is a potent inhibitor of FV infectivity in cell culture experiments. This antiviral activity is associated with cytidine editing of the viral genome. Both molecular FV clones and primary uncloned viruses were susceptible to APOBEC3G, and viral infectivity was also inhibited by murine and simian APOBEC3G homologues, as well as by human APOBEC3F. Wild-type and bet-deleted viruses were similarly sensitive to this antiviral activity, suggesting that Bet does not significantly counteract APOBEC proteins. Moreover, we did not detect FV sequences that may have been targeted by APOBEC in naturally infected macaques, but we observed a few G-to-A substitutions in humans that have been accidentally contaminated by simian FV. In infected hosts, the persistence strategy employed by FV might be based on low levels of replication, as well as avoidance of cells expressing large amounts of active cytidine deaminases.
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Wiegand, Heather L., and Bryan R. Cullen. "Inhibition of Alpharetrovirus Replication by a Range of Human APOBEC3 Proteins." Journal of Virology 81, no. 24 (October 3, 2007): 13694–99. http://dx.doi.org/10.1128/jvi.01646-07.
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ABSTRACT The mammalian APOBEC3 family of cytidine deaminases includes members that can act as potent inhibitors of retroviral infectivity and retrotransposon mobility. Here, we have examined whether the alpharetrovirus Rous sarcoma virus (RSV) is susceptible to inhibition by a range of human APOBEC3 proteins. We report that RSV is highly susceptible to inhibition by human APOBEC3G, APOBEC3F, and APOBEC3B and moderately susceptible to inhibition by human APOBEC3C and APOBEC3A. For all five proteins, inhibition of RSV infectivity was associated with selective virion incorporation and with C-to-T editing of the proviral DNA minus strand. In the case of APOBEC3G, editing appeared to be critical for effective inhibition. These data represent the first report of inhibition of retroviral infectivity and induction of proviral DNA editing by human APOBEC3A and reveal that alpharetroviruses, which do not normally encounter APOBEC3 proteins in their avian hosts, are susceptible to inhibition by all human APOBEC3 proteins tested. These data further suggest that the resistance of mammalian retroviruses to inhibition by the APOBEC3 proteins expressed in their normal host species is likely to have evolved subsequent to the appearance of this family of mammalian antiretroviral proteins some 35 million years ago; i.e., the base state of a naïve retrovirus is susceptibility to inhibition.
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Zheng, Yong-Hui, Dan Irwin, Takeshi Kurosu, Kenzo Tokunaga, Tetsutaro Sata, and B. Matija Peterlin. "Human APOBEC3F Is Another Host Factor That Blocks Human Immunodeficiency Virus Type 1 Replication." Journal of Virology 78, no. 11 (June 1, 2004): 6073–76. http://dx.doi.org/10.1128/jvi.78.11.6073-6076.2004.
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ABSTRACT Recently, APOBEC3G has been identified as a host factor that blocks retroviral replication. It introduces G to A hypermutations in newly synthesized minus strand viral cDNA at the step of reverse transcription in target cells. Here, we identified the human APOBEC3F protein as another host factor that blocks human immunodeficiency virus type 1 (HIV-1) replication. Similar to APOBEC3G, APOBEC3F also induced G to A hypermutations in HIV genomic DNA, and the viral Vif protein counteracted its activity. Thus, APOBEC family members might have evolved as a general defense mechanism of the body against retroviruses, retrotransposons, and other mobile genetic elements.
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Walker, Brian A., Christopher P. Wardell, Alexander Murison, Eileen M. Boyle, Lorenzo Melchor, Charlotte Pawlyn, Martin F. Kaiser, et al. "Apobec Family Mutational Signatures Are Associated with Poor Prognosis Translocations in Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 723. http://dx.doi.org/10.1182/blood.v124.21.723.723.
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Abstract Aberrant chromosomal translocations are seen in ~40% of presenting patients and predominantly involve the IGH locus at 14q32. The five main translocations involving the IGH locus are t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20), which result in over-expression of MMSET/FGFR3, CCND3, CCND1, MAF and MAFB, respectively. In previous clinical trials we have shown that the t(4;14), t(14;16) and t(14;20) are associated with a poor prognosis. In initial sequencing studies of myeloma it has been noted that the spectrum of mutations fall into two groups, one of which is characterised by an APOBEC signature. This signature comprises of C>T, C>G and C>A mutations in a TpC context and comprises only a subset of samples, with the rest having a rather generic mutation signature representing an intrinsic mutational process occurring as a result of the spontaneous deamination of methylated cytosine to thymine. Whole exome sequencing was performed on 463 presentation patients enrolled into the UK Myeloma XI trial. DNA was extracted from germline DNA and CD138+ plasma cells and whole exome sequencing was performed using SureSelect (Agilent). In addition to capturing the exome, extra baits were added covering the IGH, IGK, IGL and MYCloci in order to determine the breakpoints associated with translocations in these genes. Tumor and germline DNA were sequenced to a median of 60x and data processed to generate copy number, acquired variants and translocation breakpoints in the tumor. Progression-free and overall survival was measured from initial randomization and median follow up for this analysis was 25 months. These combined data allow us to examine the effect of translocations on the mutational spectra in myeloma and determine any associations with progression-free or overall survival. Translocations were detected in 232 (50.1%) patients of which 59 patients (12.7%) had a t(4;14), 86 patients (18.6%) a t(11;14), 17 patients (3.7%) a t(14;16), 5 patients (1%) a t(6;14) and 4 patients (0.9%) a t(14;20). MYC translocations were found in 85 patients (18.4%). Using the tiled regions we were able to detect a mutational signature, kataegis, where regional clustering of mutations can be indicative of somatic genomic rearrangements. We found the hallmarks of kataegis in 15 samples (3.2%), where there was enrichment for TpCpH mutations with an inter-mutational distance <1 kb. Where we detected kataegis surrounding MYC there was also an inter-chromosomal translocation involving either IGK or IGL. Interestingly, the partner chromosomes also showed signs of kataegis e.g. in the t(2;8) kataegis was found at IGK and MYC and in the t(8;22) kataegis was found at MYC and IGL. APOBECs are thought to be involved in the generation of kataegis and as such this co-localisation is indicative of APOBEC involvement in the generation of MYCbreakpoints. We found mutation of translocation partner oncogenes, in particular CCND1 was mutated in 10 patients with the t(11;14). There was an association of mutated CCND1 with a poor prognosis when compared with non-mutated t(11;14) patients (OS median of 20.2 months vs. not reached, p=0.005). Mutations were also seen in FGFR3, MAF and MAFB but only in the samples with the respective translocations. The mutations are likely due to somatic hypermutation mediated by AID, an APOBEC family member. We found that t(14;16) and t(14;20) samples have a significantly higher number of mutations compare to the other translocation groups (p=1.65x10-5). These mutations were enriched for those with an APOBEC signature (T(C>T)A, p=9.1x10-5; T(C>T)T, p=0.0014; T(C>G)A, p=0.001; T(C>G)T, p=0.0064), indicating that the ‘maf’ translocation groups are characterized by APOBEC signature mutations, specifically APOBEC3B. When samples are assigned to either an APOBEC or non-APOBEC group the ‘maf’ translocations account for 66.6% of samples in the APOBEC group but only 1.3% of the non-APOBEC group. Here we show three different mutational signatures mediated by the APOBEC family: translocation partner mutation by AID, APOBEC signature mediated by APOBEC3B, and kataegis mediated by an unknown APOBEC family member. We also show for the first time a clinical impact of APOBEC mutations and their association with a poor prognosis. The poor prognosis of this mutational signature is inextricably linked to a high mutation load and the adverse t(14;16) and t(14;20) translocation subgroups. Disclosures Walker: Onyx Pharmaceuticals: Consultancy, Honoraria.
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Malim, Michael H. "APOBEC proteins and intrinsic resistance to HIV-1 infection." Philosophical Transactions of the Royal Society B: Biological Sciences 364, no. 1517 (November 27, 2008): 675–87. http://dx.doi.org/10.1098/rstb.2008.0185.
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Members of the APOBEC family of cellular polynucleotide cytidine deaminases, most notably APOBEC3G and APOBEC3F, are potent inhibitors of HIV-1 infection. Wild type HIV-1 infections are largely spared from APOBEC3G/F function through the action of the essential viral protein, Vif. In the absence of Vif, APOBEC3G/F are encapsidated by budding virus particles leading to excessive cytidine (C) to uridine (U) editing of negative sense reverse transcripts in newly infected cells. This registers as guanosine (G) to adenosine (A) hypermutations in plus-stranded cDNA. In addition to this profoundly debilitating effect on genetic integrity, APOBEC3G/F also appear to inhibit viral DNA synthesis by impeding the translocation of reverse transcriptase along template RNA. Because the functions of Vif and APOBEC3G/F proteins oppose each other, it is likely that fluctuations in the Vif–APOBEC balance may influence the natural history of HIV-1 infection, as well as viral sequence diversification and evolution. Given Vif's critical role in suppressing APOBEC3G/F function, it can be argued that pharmacologic strategies aimed at restoring the activity of these intrinsic anti-viral factors in the context of infected cells in vivo have clear therapeutic merit, and therefore deserve aggressive pursuit.
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Wurtzer, Sebastien, Armelle Goubard, Fabrizio Mammano, Sentob Saragosti, Denise Lecossier, Allan J. Hance, and François Clavel. "Functional Central Polypurine Tract Provides Downstream Protection of the Human Immunodeficiency Virus Type 1 Genome from Editing by APOBEC3G and APOBEC3B." Journal of Virology 80, no. 7 (April 1, 2006): 3679–83. http://dx.doi.org/10.1128/jvi.80.7.3679-3683.2006.
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ABSTRACT Lentiviruses utilize two polypurine tracts for initiation of plus-strand viral DNA synthesis. We have examined to what extent human immunodeficiency virus type 1 plus-strand initiation at the central polypurine tract (cPPT) could protect the viral genome from DNA editing by APOBEC3G and APOBEC3B. The presence of a functional cPPT, but not of a mutated cPPT, extensively reduced editing by both APOBEC3G and APOBEC3B of sequences downstream, but not upstream, of the cPPT, with significant protection observed as far as 400 bp downstream. Thus, in addition to other potential functions, the cPPT could help protect lentiviruses from editing by cytidine deaminases of the APOBEC family.
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Vieira, Valdimara C., and Marcelo A. Soares. "The Role of Cytidine Deaminases on Innate Immune Responses against Human Viral Infections." BioMed Research International 2013 (2013): 1–18. http://dx.doi.org/10.1155/2013/683095.
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The APOBEC family of proteins comprises deaminase enzymes that edit DNA and/or RNA sequences. The APOBEC3 subgroup plays an important role on the innate immune system, acting on host defense against exogenous viruses and endogenous retroelements. The role of APOBEC3 proteins in the inhibition of viral infection was firstly described for HIV-1. However, in the past few years many studies have also shown evidence of APOBEC3 action on other viruses associated with human diseases, including HTLV, HCV, HBV, HPV, HSV-1, and EBV. APOBEC3 inhibits these viruses through a series of editing-dependent and independent mechanisms. Many viruses have evolved mechanisms to counteract APOBEC effects, and strategies that enhance APOBEC3 activity constitute a new approach for antiviral drug development. On the other hand, novel evidence that editing by APOBEC3 constitutes a source for viral genetic diversification and evolution has emerged. Furthermore, a possible role in cancer development has been shown for these host enzymes. Therefore, understanding the role of deaminases on the immune response against infectious agents, as well as their role in human disease, has become pivotal. This review summarizes the state-of-the-art knowledge of the impact of APOBEC enzymes on human viruses of distinct families and harboring disparate replication strategies.
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Holland, Stephen J., Lesley M. Berghuis, Justin J. King, Lakshminarayan M. Iyer, Katarzyna Sikora, Heather Fifield, Sarah Peter, et al. "Expansions, diversification, and interindividual copy number variations of AID/APOBEC family cytidine deaminase genes in lampreys." Proceedings of the National Academy of Sciences 115, no. 14 (March 19, 2018): E3211—E3220. http://dx.doi.org/10.1073/pnas.1720871115.
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Cytidine deaminases of the AID/APOBEC family catalyze C-to-U nucleotide transitions in mRNA or DNA. Members of the APOBEC3 branch are involved in antiviral defense, whereas AID contributes to diversification of antibody repertoires in jawed vertebrates via somatic hypermutation, gene conversion, and class switch recombination. In the extant jawless vertebrate, the lamprey, two members of the AID/APOBEC family are implicated in the generation of somatic diversity of the variable lymphocyte receptors (VLRs). Expression studies linked CDA1 and CDA2 genes to the assembly of VLRA/C genes in T-like cells and the VLRB genes in B-like cells, respectively. Here, we identify and characterize several CDA1-like genes in the larvae of different lamprey species and demonstrate that these encode active cytidine deaminases. Structural comparisons of the CDA1 variants highlighted substantial differences in surface charge; this observation is supported by our finding that the enzymes require different conditions and substrates for optimal activity in vitro. Strikingly, we also found that the number of CDA-like genes present in individuals of the same species is variable. Nevertheless, irrespective of the number of different CDA1-like genes present, all lamprey larvae have at least one functional CDA1-related gene encoding an enzyme with predicted structural and chemical features generally comparable to jawed vertebrate AID. Our findings suggest that, similar to APOBEC3 branch expansion in jawed vertebrates, the AID/APOBEC family has undergone substantial diversification in lamprey, possibly indicative of multiple distinct biological roles.
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Chen, Xiaojiang S. "Insights into the Structures and Multimeric Status of APOBEC Proteins Involved in Viral Restriction and Other Cellular Functions." Viruses 13, no. 3 (March 17, 2021): 497. http://dx.doi.org/10.3390/v13030497.
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Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins belong to a family of deaminase proteins that can catalyze the deamination of cytosine to uracil on single-stranded DNA or/and RNA. APOBEC proteins are involved in diverse biological functions, including adaptive and innate immunity, which are critical for restricting viral infection and endogenous retroelements. Dysregulation of their functions can cause undesired genomic mutations and RNA modification, leading to various associated diseases, such as hyper-IgM syndrome and cancer. This review focuses on the structural and biochemical data on the multimerization status of individual APOBECs and the associated functional implications. Many APOBECs form various multimeric complexes, and multimerization is an important way to regulate functions for some of these proteins at several levels, such as deaminase activity, protein stability, subcellular localization, protein storage and activation, virion packaging, and antiviral activity. The multimerization of some APOBECs is more complicated than others, due to the associated complex RNA binding modes.
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Ghorbani, Atefeh, Justin J. King, and Mani Larijani. "The optimal pH of AID is skewed from that of its catalytic pocket by DNA-binding residues and surface charge." Biochemical Journal 479, no. 1 (January 6, 2022): 39–55. http://dx.doi.org/10.1042/bcj20210529.
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Activation-induced cytidine deaminase (AID) is a member of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of cytidine deaminases. AID mutates immunoglobulin loci to initiate secondary antibody diversification. The APOBEC3 (A3) sub-branch mutates viral pathogens in the cytosol and acidic endosomal compartments. Accordingly, AID functions optimally near-neutral pH, while most A3s are acid-adapted (optimal pH 5.5–6.5). To gain a structural understanding for this pH disparity, we constructed high-resolution maps of AID catalytic activity vs pH. We found AID's optimal pH was 7.3 but it retained most (>70%) of the activity at pH 8. Probing of ssDNA-binding residues near the catalytic pocket, key for bending ssDNA into the pocket (e.g. R25) yielded mutants with altered pH preference, corroborating previous findings that the equivalent residue in APOBEC3G (H216) underlies its acidic pH preference. AID from bony fish exhibited more basic optimal pH (pH 7.5–8.1) and several R25-equivalent mutants altered pH preference. Comparison of pH optima across the AID/APOBEC3 family revealed an inverse correlation between positive surface charge and overall catalysis. The paralogue with the most robust catalytic activity (APOBEC3A) has the lowest surface charge and most acidic pH preference, while the paralogue with the most lethargic catalytic rate (AID) has the most positive surface charge and highest optimal pH. We suggest one possible mechanism is through surface charge dictating an overall optimal pH that is different from the optimal pH of the catalytic pocket microenvironment. These findings illuminate an additional structural mechanism that regulates AID/APOBEC3 mutagenesis.
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Blanc, Valerie, Jeffrey O. Henderson, Elizabeth P. Newberry, Susan Kennedy, Jianyang Luo, and Nicholas O. Davidson. "Targeted Deletion of the Murine apobec-1 Complementation Factor (acf) Gene Results in Embryonic Lethality." Molecular and Cellular Biology 25, no. 16 (August 15, 2005): 7260–69. http://dx.doi.org/10.1128/mcb.25.16.7260-7269.2005.
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ABSTRACT apobec-1 complementation factor (ACF) is an hnRNP family member which functions as the obligate RNA binding subunit of the core enzyme mediating C-to-U editing of the nuclear apolipoprotein B (apoB) transcript. ACF binds to both apoB RNA and apobec-1, the catalytic cytidine deaminase, which then results in site-specific posttranscriptional editing of apoB mRNA. Targeted deletion of apobec1 eliminates C-to-U editing of apoB mRNA but is otherwise well tolerated. However, the functions and potential targets of ACF beyond apoB mRNA editing are unknown. Here we report the results of generating acf knockout mice using homologous recombination. While heterozygous acf +/ − mice were apparently healthy and fertile, no viable acf − / − mice were identified. Mutant acf − / − embryos were detectable only until the blastocyst (embryonic day 3.5 [E3.5]) stage. No acf − / − blastocysts were detectable following implantation at E4.5, and isolated acf − / − blastocysts failed to proliferate in vitro. Small interfering RNA knockdown of ACF in either rat (apobec-1-expressing) or human (apobec-1-deficient) hepatoma cells decreased ACF protein expression and induced a commensurate increase in apoptosis. Taken together, these data suggest that ACF plays a crucial role, which is independent of apobec-1 expression, in cell survival, particularly during early embryonic development.
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Stewart, Jessica A., Grant Schauer, and Ashok S. Bhagwat. "Visualization of uracils created by APOBEC3A using UdgX shows colocalization with RPA at stalled replication forks." Nucleic Acids Research 48, no. 20 (October 19, 2020): e118-e118. http://dx.doi.org/10.1093/nar/gkaa845.
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Abstract The AID/APOBEC enzymes deaminate cytosines in single-stranded DNA (ssDNA) and play key roles in innate and adaptive immunity. The resulting uracils cause mutations and strand breaks that inactivate viruses and diversify antibody repertoire. Mutational evidence suggests that two members of this family, APOBEC3A (A3A) and APOBEC3B, deaminate cytosines in the lagging-strand template during replication. To obtain direct evidence for the presence of these uracils, we engineered a protein that covalently links to DNA at uracils, UdgX, for mammalian expression and immunohistochemistry. We show that UdgX strongly prefers uracils in ssDNA over those in U•G or U:A pairs, and localizes to nuclei in a dispersed form. When A3A is expressed in these cells, UdgX tends to form foci. The treatment of cells with cisplatin, which blocks replication, causes a significant increase in UdgX foci. Furthermore, this protein- and hence the uracils created by A3A- colocalize with replication protein A (RPA), but not with A3A. Using purified proteins, we confirm that RPA inhibits A3A by binding ssDNA, but despite its overexpression following cisplatin treatment, RPA is unable to fully protect ssDNA created by cisplatin adducts. This suggests that cisplatin treatment of cells expressing APOBEC3A should cause accumulation of APOBEC signature mutations.
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Mayekar, Manasi, Deborah Caswell, Natalie Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, et al. "Abstract 2197: Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2197. http://dx.doi.org/10.1158/1538-7445.am2022-2197.
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Abstract Introduction: Increasing our understanding of drivers of mutagenesis in lung cancer is critical in our efforts to prevent tumor reoccurrence and resistance. Results: Using the multi-region TRACERx lung cancer study, we uncovered that APOBEC3B is significantly upregulated when compared with other APOBEC family members in EGFR driven lung cancer and identified subclonal enrichment of APOBEC mutational signatures. To model APOBEC mutagenesis in lung cancer, several novel EGFR mutant mouse models containing a human APOBEC3B transgene were generated. Using these models, it was uncovered that APOBEC3B expression is detrimental at tumor initiation when expressed continuously in a p53 wildtype background. This detrimental effect is likely due to elevated chromosomal instability, which was observed to increase significantly with APOBEC3B expression in an EGFR mutant TP53 deficient mouse model. Induction of subclonal expression of APOBEC3B in an EGFR mutant mouse model with tyrosine kinase inhibitor (TKI) therapy resulted in a significant increase in resistant tumor development. Significant downregulation of the base excision repair gene uracil-DNA glycosylase (UNG) was also observed in APOBEC3B expressing mice, which paralleled findings in patient tumors and cell lines treated with TKI therapy. Finally, a mouse mutational signature was identified in APOBEC3B expressing cell lines, reinforcing the idea that APOBEC driven mutagenesis contributes to TKI resistance. Conclusion: This study demonstrates a unique principle by which targeted therapy induces changes within tumors ideal for APOBEC driven tumor evolution, fueling therapy resistance. Citation Format: Manasi Mayekar, Deborah Caswell, Natalie Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Clare Weeden, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, Daniel L. Kerr, Julia K. Rotow, Oriol Pich, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanj, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nicholas McGranahan, Nnennaya Kanu, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever Bivona, Charles Swanton. Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2197.
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Siu, Karen, Azmiri Sultana, Farshad Azimi, and Jeffrey Lee. "Structural determinants of ssDNA- and HIV-1 Vif-binding in APOBEC3F." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C118. http://dx.doi.org/10.1107/s2053273314098817.
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The human APOBEC3 family of DNA cytosine deaminases serves as a front-line intrinsic immune response to inhibit the replication of diverse retroviruses. APOBEC3F and APOBEC3G are the most potent factors against HIV-1. As a countermeasure, HIV-1 viral infectivity factor (Vif) targets APOBEC3s for proteasomal degradation. Here, we report the crystal structure of the Vif-binding domain in APOBEC3F and a novel assay to assess Vif-APOBEC3 binding. Our results reveal a conserved, amphipathic surface in APOBEC3s that is critical for Vif binding. APOBEC3F-Vif interaction is likely mediated via electrostatic interactions. Moreover, structure-guided mutagenesis reveals a straight ssDNA-binding groove in APOBEC3F, and an `aromatic switch' is proposed to explain the different DNA substrate specificities across the APOBEC3 family. This study opens new lines of inquiry that will further our understanding of APOBEC3-mediated retroviral restriction and provides an accurate template for structure-guided development of inhibitors targeting the APOBEC3-Vif axis.
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Takaori-Kondo, Akifumi. "APOBEC Family Proteins: Novel Antiviral Innate Immunity." International Journal of Hematology 83, no. 3 (April 1, 2006): 213–16. http://dx.doi.org/10.1532/ijh97.05187.
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Riva, Giuseppe, Camilla Albano, Francesca Gugliesi, Selina Pasquero, Sergio Fernando Castillo Pacheco, Giancarlo Pecorari, Santo Landolfo, Matteo Biolatti, and Valentina Dell’Oste. "HPV Meets APOBEC: New Players in Head and Neck Cancer." International Journal of Molecular Sciences 22, no. 3 (January 30, 2021): 1402. http://dx.doi.org/10.3390/ijms22031402.
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Besides smoking and alcohol, human papillomavirus (HPV) is a factor promoting head and neck squamous cell carcinoma (HNSCC). In some human tumors, including HNSCC, a number of mutations are caused by aberrantly activated DNA-modifying enzymes, such as the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) family of cytidine deaminases. As the enzymatic activity of APOBEC proteins contributes to the innate immune response to viruses, including HPV, the role of APOBEC proteins in HPV-driven head and neck carcinogenesis has recently gained increasing attention. Ongoing research efforts take the cue from two key observations: (1) APOBEC expression depends on HPV infection status in HNSCC; and (2) APOBEC activity plays a major role in HPV-positive HNSCC mutagenesis. This review focuses on recent advances on the role of APOBEC proteins in HPV-positive vs. HPV-negative HNSCC.
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Doehle, Brian P., Alexandra Schäfer, Heather L. Wiegand, Hal P. Bogerd, and Bryan R. Cullen. "Differential Sensitivity of Murine Leukemia Virus to APOBEC3-Mediated Inhibition Is Governed by Virion Exclusion." Journal of Virology 79, no. 13 (July 1, 2005): 8201–7. http://dx.doi.org/10.1128/jvi.79.13.8201-8207.2005.
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ABSTRACT While members of the APOBEC3 family of human intrinsic resistance factors are able to restrict the replication of Vif-deficient forms of human immunodeficiency virus type 1 (HIV-1), they are unable to block replication of wild-type HIV-1 due to the action of Vif, which induces their degradation. In contrast, HIV-1 Vif is unable to block inhibition mediated by APOBEC3 proteins expressed by several heterologous species, including mice. Here, we have asked whether the simple retrovirus murine leukemia virus (MLV) is sensitive to restriction by the cognate murine or heterologous, human APOBEC3 proteins. We demonstrate that MLV is highly sensitive to inhibition by human APOBEC3G and APOBEC3B but resistant to inhibition by murine APOBEC3 or by other human APOBEC3 proteins, including APOBEC3F. This sensitivity fully correlates with the ability of these proteins to be packaged into MLV virion particles: i.e., human APOBEC3G and APOBEC3B are packaged while murine APOBEC3 and human APOBEC3F are excluded. Moreover, this packaging in turn correlates with the differential ability of these APOBEC3 proteins to bind MLV Gag. Together, these data suggest that MLV Gag has evolved to avoid binding, and hence virion packaging, of the cognate murine APOBEC3 protein but that MLV infectivity is still restricted by certain heterologous APOBEC3 proteins that retain this ability. Moreover, these results suggest that APOBEC3 proteins may help prevent the zoonotic infection of humans by simple retroviruses and provide a mechanism for how simple retroviruses can avoid inhibition by APOBEC3 family members.
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Lerner, Taga, F. Papavasiliou, and Riccardo Pecori. "RNA Editors, Cofactors, and mRNA Targets: An Overview of the C-to-U RNA Editing Machinery and Its Implication in Human Disease." Genes 10, no. 1 (December 27, 2018): 13. http://dx.doi.org/10.3390/genes10010013.
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One of the most prevalent epitranscriptomic modifications is RNA editing. In higher eukaryotes, RNA editing is catalyzed by one of two classes of deaminases: ADAR family enzymes that catalyze A-to-I (read as G) editing, and AID/APOBEC family enzymes that catalyze C-to-U. ADAR-catalyzed deamination has been studied extensively. Here we focus on AID/APOBEC-catalyzed editing, and review the emergent knowledge regarding C-to-U editing consequences in the context of human disease.
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Anant, Shrikant, Debnath Mukhopadhyay, Vakadappu Sankaranand, Susan Kennedy, Jeffrey O. Henderson, and Nicholas O. Davidson. "ARCD-1, an apobec-1-related cytidine deaminase, exerts a dominant negative effect on C to U RNA editing." American Journal of Physiology-Cell Physiology 281, no. 6 (December 1, 2001): C1904—C1916. http://dx.doi.org/10.1152/ajpcell.2001.281.6.c1904.
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Mammalian apolipoprotein B (apoB) C to U RNA editing is catalyzed by a multicomponent holoenzyme containing a single catalytic subunit, apobec-1. We have characterized an apobec-1 homologue, ARCD-1, located on chromosome 6p21.1, and determined its role in apoB mRNA editing. ARCD-1 mRNA is ubiquitously expressed; phylogenetic analysis reveals it to be a distant member of the RNA editing family. Recombinant ARCD-1 demonstrates cytidine deaminase and apoB RNA binding activity but does not catalyze C to U RNA editing, either in vitro or in vivo. Although not competent itself to mediate deamination of apoB mRNA, ARCD-1 inhibits apobec-1-mediated C to U RNA editing. ARCD-1 interacts and heterodimerizes with both apobec-1 and apobec-1 complementation factor (ACF) and localizes to both the nucleus and cytoplasm of transfected cells. Together, the data suggest that ARCD-1 is a novel cytidine deaminase that interacts with apobec-1 and ACF to inhibit apoB mRNA editing, possibly through interaction with other protein components of the apoB RNA editing holoenzyme.
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Shapiro, Kate, Maxwell Shapiro, and Thomas MacCarthy. "#84: Evolutionary Pressure from APOBEC Causes an Underrepresentation of TC Motifs in Human Polyomavirus." Journal of the Pediatric Infectious Diseases Society 10, Supplement_1 (March 1, 2021): S14—S15. http://dx.doi.org/10.1093/jpids/piaa170.043.
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Abstract Background Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) is a family of enzymes found in mammals that deaminate cytidine to uridine on ssDNA, facilitating a C-to-T mutation. Less commonly, APOBEC effectively mutates C-to-G as well. APOBEC has the potential to mutate the viral genome, rendering the virus nonproductive. The enzyme targets certain mutational motifs, also known as hotspots: most APOBECs deaminate at TC motifs. We hypothesize that human polyomaviruses (hPyV) have an under-representation of TC hotspots in their genomes to avoid APOBEC targeting. Specifically, we analyzed the degree of TC motif under-representation in five conserved genes of hPyV, each of which is expressed in either the early or late phase of the viral life cycle. Methods We utilized a statistical tool, the Cytidine Deaminase Under-representation Reporter (CDUR) that can be used to analyze sequences and determine whether these sequences have mutated under the evolutionary pressure of APOBEC based on the targeted hotspot. This tool uses a permutation test to determine whether the number of hotspots at a given coding sequence is significantly more or significantly less than expected under pseudo-random biological sequence evolution. The same analysis was used to determine whether the number of nonsynonymous mutations that might occur at those hotspots is significantly more or significantly less than expected by chance. Results TC motifs in early genes were more underrepresented compared with late genes in most hPyV species. Most early genes were susceptible to nonsynonymous mutations at the TC motifs. Those species which did not fit into this paradigm showed a similar degree of under-representation and susceptibility to nonsynonymous mutations at AC motifs. We also find a large over-representation of TG hotspots, but not TT hotspots. Conclusions hPyV may have evolved a reduced number of hotspots to subvert APOBEC and evade host immune defenses. Under-representation of TC motifs is more prevalent in early genes. Early genes include the small T and large T antigens, essential for viral proliferation. In addition, the large T antigen was particularly susceptible to mutation at TC motifs. This underscores the evolutionary pressure imposed on hPyV by APOBEC to evade host immunity. It is possible that the over-representation of TG motifs in hPyV is due to specific host DNA-repair mechanisms, but this requires further investigation.
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Pilzecker, Bas, Olimpia Alessandra Buoninfante, Colin Pritchard, Olga S. Blomberg, Ivo J. Huijbers, Paul C. M. van den Berk, and Heinz Jacobs. "PrimPol prevents APOBEC/AID family mediated DNA mutagenesis." Nucleic Acids Research 44, no. 10 (February 28, 2016): 4734–44. http://dx.doi.org/10.1093/nar/gkw123.
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Conticello, Silvestro G. "The AID/APOBEC family of nucleic acid mutators." Genome Biology 9, no. 6 (2008): 229. http://dx.doi.org/10.1186/gb-2008-9-6-229.
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Kazuma, Yasuhiro, Kotaro Shirakawa, Anamaria Daniela Sarca, Yoshihito Horisawa, Hirofumi Fukuda, Hiroyuki Matsui, Hiroyuki Yamazaki, et al. "Interactome Analysis of APOBEC3B in Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 1259. http://dx.doi.org/10.1182/blood-2019-126856.
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Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) family proteins restrict retroviruses and retrotransposons by inducing hypermutation or degradation of the replication intermediates through their DNA cytidine deaminase activity. APOBECs can also act as endogenous sources of DNA damage that mutate many human cancers. Accumulation of APOBEC signature mutations is associated with disease progression and poor overall survival in multiple myeloma (Walker et al. Nat Commun, 2015). Among APOBEC3 enzymes, APOBEC3B (A3B) is the only family member that is predominantly located in the nucleus throughout the cell cycle. We previously reported that A3B knockdown decreased cytidine deaminase activity in myeloma cells, suggesting that among APOBECs, A3B plays a major role in cytidine deamination-related mutagenesis in myeloma cells (Yamazaki et al., Sci Rep, 2019). Recent studies showed that cofactors of A3B could affect the functions of A3B: heterogeneous nuclear ribonucleoproteins (hnRNPs) interact with surface hydrophobic residues of the N-terminal domain in order to bind to A3B (Xiao et al., Nuc. Acids Res, 2017; Zhang al., Cell Microbiol, 2008); BORF2, an Epstein-Barr viral protein, interacts with the A3B catalytic domain and inhibits A3B DNA cytidine deaminase activity (Cheng et al., Nat Microbiol, 2018). However, the biological mechanisms of how endogenous A3B induces mutations in genomic DNA are still unclear. In this study, we aim to ascertain the cofactors for nucleic acid binding and elucidate the regulatory mechanisms that prevent APOBEC-mediated genomic mutagenesis. Because of the high homology between APOBEC3 proteins, a specific antibody against A3B is not available, and it is difficult to analyze A3B-interaction at the endogenous expression level. To overcome this technical impediment, we used a lentiCRISPR system to insert a FLAG-tag sequence at the C-terminus of the A3B gene in A3B highly expressing myeloma cell lines (AMO1 and RPMI8226). We then conducted A3B-immunoprecipitation with the anti-FLAG M2 antibody, followed by mass spectrometry (MS) analysis to identify potential A3B interacting proteins. MS analysis identified 40 putative interacting proteins and these proteins were clustered largely into two interaction networks: ribonucleoprotein complex and ribosomal-associated proteins. We also performed Gene Ontology (GO) enrichment analysis and revealed that spliceosome, ribosome, and RNA transport were significantly enriched terms. We confirmed the binding between A3B and selected A3B interacting proteins: hnRNPs, interleukin enhancer-binding factor 2 and 3 (ILF2, ILF3) in myeloma cell lines by co-immunoprecipitation assays. Next, we tested the intracellular colocalization of overexpressed A3B and interacting proteins in Hela cells by immunofluorescence microscopy. We found that ILF2 presents strong colocalization with A3B in the nuclei of cells. We also employed density-gradient sedimentation analysis to test if these proteins form high molecular mass (HMM) complexes with A3B in the nucleus using HEK293T cells expressing FLAG-tagged A3B. We detected that ILF2 is one of the components of HMM A3B complexes. To check whether these putative interacting proteins affect A3B cytidine deaminase activity, we next performed an in vitro luminescence-based screening assay (AlphaScreen)using a FLAG-GST protein library which was produced by the wheat cell-free protein production system. We found that hnRNP A1 and ILF2 decreased A3B cytidine deaminase activity. This study provides for the first time a proteomic characterization of A3B interactome in a myeloma cell context. Our findings reveal putative A3B cofactors in myeloma cell lines which may regulate the catalytic activity of A3B. We discuss how these proteins bind A3B and affect its activity in myeloma cells. Disclosures Takaori-Kondo: Pfizer: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono: Research Funding; Takeda: Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding.
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Chu, Charles C., Piers E. M. Patten, Thomas MacCarthy, Chaohui Yuan, Xiao-Jie Yan, Jacqueline C. Barrientos, Jonathan E. Kolitz, Steven L. Allen, Kanti R. Rai, and Nicholas Chiorazzi. "IGHV-D-J Ultra-Deep Sequencing Reveals APOBEC and AID Targeted Mutations during Clonal Evolution of CLL in a Xenograft Mouse Model." Blood 124, no. 21 (December 6, 2014): 300. http://dx.doi.org/10.1182/blood.v124.21.300.300.
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Abstract Targeted ultra-deep sequencing of chronic lymphocytic leukemia (CLL) cells has enabled the assessment of subclone development based on mutations in the IGHV-D-J signature sequence in the dominant CLL clone. We have utilized the Roche 454 FLX pyrosequencing system, which can generate long sequencing reads containing both the immunoglobulin variable region (IGHV-D-J) and part of the immunoglobulin μ constant region (IGHM) in a single sequence, to analyze the mutational characteristics of newly evolved subclones to determine if they derive from AID/APOBEC activity. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) is a family of cytidine deaminases that includes AID (activation-induced cytidine deaminase). AID is required for somatic hypermutation in germinal center B lymphocytes. CLL cells, like most non-germinal center B lymphocytes, generally do not express AID. However, AID expression in a small fraction of the CLL clone correlates with worse patient outcome. This observation has led to the hypothesis that abnormal AID expression promotes new off-target non-immunoglobulin mutations and DNA deletions and rearrangements leading to the development of more aggressive disease. CLL is not alone in this hypothesis, as AID is involved in the evolution of other leukemias/lymphomas and reportedly in other types of tumors such as breast and gastrointestinal cancers. Large scale cataloguing of somatic mutations by ultra-deep sequencing of a wide array of cancers has revealed an AID/APOBEC mutational signature in many cancers, including CLL (Alexandrov et al. 2013 Nature). Thus, AID/APOBEC family members may be involved in somatic mutations leading to the evolution of aggressive cancers. To test if AID/APOBEC proteins could be mutationally active in CLL, we analyzed the characteristics of new mutations found in IGHV-D-J-M in CLL cells that were activated in vivo after adoptive transfer into alymphoid NOD/Shi-scid,γcnull (NSG) mice. This CLL xenograft model activates a large fraction of CLL cells, which become AID+ and facilitates the detection of new subclones expressing mutated IGHV-D-Js by ultra-deep sequencing. Four unmutated IGHV CLL (U-CLL) and 3 mutated IGHV (>2% compared to germline) CLL (M-CLL) samples were each adoptively transferred into individual NSG mice. After expansion of CLL, the mice were sacrificed and the specific CLL clone IGHV-D-J-M was amplified from xenograft mouse spleen cDNA. Pre-transfer CLL cell cDNA was also amplified to establish a baseline comparison. Ultra-deep sequencing of these samples resulted in 2,318,800 sequence reads, which were subsequently trimmed according to the Roche 454 algorithm and further processed by custom R scripts. The sequence reads were aligned to the dominant CLL clone IGHV-D-J-M sequence to remove insertions, deletions, and poor quality (<20) nucleotides, resulting in 1,700,839 blocks of sequences of the same length. The dominant CLL clones represented 92.3% (1,569,059 blocks) of these sequences and were excluded. Mutated subclone sequences that occurred at least twice were extracted. Xenograft subclones not found in the pre-transfer sample were selected for analyses of the characteristics of newly generated CLL mutations. New xenograft CLL subclones could be identified in all samples (3.2 – 12.3 new subclones / read bp *106). AID mutational characteristics in new subclones were assessed using the SHMTool (http://scb.aecom.yu.edu/shmtool) algorithms to calculate mutation frequencies in IGHV-D-J relative to IGHM and at AID mutation hotspots and coldspots. Other APOBEC family members have a different mutation hotspot site, which we analyzed by custom R scripts. All CLL samples showed evidence of AID mutational activity: higher IGHV-D-J versus IGHM mutations in all cases, increased AID hotspot mutation frequency in five cases, and decreased AID coldspot mutation frequency in five cases. Increased APOBEC hotspot mutational activity was seen in four cases. This APOBEC mutational activity is consistent with increased APOBEC3 gene expression and the genomic somatic mutation pattern observed recently in CLL (Rebhandl et al. 2014 Leukemia). Thus, both U-CLL and M-CLL are capable of producing mutations characteristic of AID or APOBEC activity. These data are consistent with the hypothesis that AID/APOBEC may promote new mutations leading to the evolution of aggressive CLL. Disclosures No relevant conflicts of interest to declare.
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Browne, Edward P., and Dan R. Littman. "Species-Specific Restriction of Apobec3-Mediated Hypermutation." Journal of Virology 82, no. 3 (November 21, 2007): 1305–13. http://dx.doi.org/10.1128/jvi.01371-07.
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ABSTRACT Apobec proteins are a family of cellular cytidine deaminases, among which several members have been shown to have potent antiviral properties. This antiviral activity is associated with the ability to cause hypermutation of retroviral cDNA. However, recent research has indicated that Apobec proteins are also able to inhibit retroviruses by other mechanisms that are independent of their deaminase activity. We have compared the antiviral activities of human and murine Apobec3 (A3) proteins, and we have found that, consistent with previous reports, human immunodeficiency virus (HIV) is able to resist human A3G but is sensitive to murine A3, whereas murine leukemia virus (MLV) is relatively resistant to murine A3 (mA3) but sensitive to human A3G. In contrast to previous studies, we observed that mA3 is packaged efficiently into MLV particles. The C-terminal cytidine deaminase domain (CDD2) is required for packaging of mA3 into MLV particles, and packaging did not depend on the MLV viral RNA. However, mA3 packed into MLV particles failed to cause hypermutation of viral DNA, indicating that its deaminase activity is blocked or inhibited. hA3G also caused significantly less hypermutation of MLV than of HIV DNA. Both mA3 and the splice variant mA3Δ5 exhibited some residual antiviral activity against MLV and caused a reduction in the ability of MLV particles to generate reverse transcription products. These results suggest that MLV has evolved specific mechanisms to block the ability of Apobec proteins to mediate deaminase-dependent hypermutation.
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Smith, Harold C., Ryan P. Bennett, Ayse Kizilyer, William M. McDougall, and Kimberly M. Prohaska. "Functions and regulation of the APOBEC family of proteins." Seminars in Cell & Developmental Biology 23, no. 3 (May 2012): 258–68. http://dx.doi.org/10.1016/j.semcdb.2011.10.004.
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Verhalen, Brandy, Gabriel J. Starrett, Reuben S. Harris, and Mengxi Jiang. "Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses." Journal of Virology 90, no. 14 (May 4, 2016): 6379–86. http://dx.doi.org/10.1128/jvi.00771-16.
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ABSTRACTThe APOBEC3 family of DNA cytosine deaminases has important roles in innate immunity and cancer. It is unclear how DNA tumor viruses regulate these enzymes and how these interactions, in turn, impact the integrity of both the viral and cellular genomes. Polyomavirus (PyVs) are small DNA pathogens that contain oncogenic potentials. In this study, we examined the effects of PyV infection on APOBEC3 expression and activity. We demonstrate that APOBEC3B is specifically upregulated by BK polyomavirus (BKPyV) infection in primary kidney cells and that the upregulated enzyme is active. We further show that the BKPyV large T antigen, as well as large T antigens from related polyomaviruses, is alone capable of upregulating APOBEC3B expression and activity. Furthermore, we assessed the impact of A3B on productive BKPyV infection and viral genome evolution. Although the specific knockdown of APOBEC3B has little short-term effect on productive BKPyV infection, our informatics analyses indicate that the preferred target sequences of APOBEC3B are depleted in BKPyV genomes and that this motif underrepresentation is enriched on the nontranscribed stand of the viral genome, which is also the lagging strand during viral DNA replication. Our results suggest that PyV infection upregulates APOBEC3B activity to influence virus sequence composition over longer evolutionary periods. These findings also imply that the increased activity of APOBEC3B may contribute to PyV-mediated tumorigenesis.IMPORTANCEPolyomaviruses (PyVs) are a group of emerging pathogens that can cause severe diseases, including cancers in immunosuppressed individuals. Here we describe the finding that PyV infection specifically induces the innate immune DNA cytosine deaminase APOBEC3B. The induced APOBEC3B enzyme is fully functional and therefore may exert mutational effects on both viral and host cell DNA. We provide bioinformatic evidence that, consistent with this idea, BK polyomavirus genomes are depleted of APOBEC3B-preferred target motifs and enriched for the corresponding predicted reaction products. These data imply that the interplay between PyV infection and APOBEC proteins may have significant impact on both viral evolution and virus-induced tumorigenesis.
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Chelico, Linda. "Special Issue “APOBECs and Virus Restriction”." Viruses 13, no. 8 (August 15, 2021): 1613. http://dx.doi.org/10.3390/v13081613.
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Stefanovska, Bojana, Kevin Lin, Benjamin Troness, Chad Myers, and Reuben Harris. "Abstract P2-17-01: Targeted CRISPR screen to identify synthetic lethal combinations between APOBEC3B and DNA repair." Cancer Research 83, no. 5_Supplement (March 1, 2023): P2–17–01—P2–17–01. http://dx.doi.org/10.1158/1538-7445.sabcs22-p2-17-01.
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Abstract APOBEC-catalyzed deamination of cytosine bases is the largest enzymatic and second largest overall source of mutation in cancer. One member from the APOBEC family of enzymes, APOBEC3B (A3B) is overexpressed and dysregulated in many different cancer types. In addition to hallmark C-to-T transitions and C-to-G transversions, APOBEC-catalyzed uracil lesions can be processed into single- and double-strand DNA breaks. Therefore, A3B-positive tumors are under continual stress to repair DNA breaks and may be vulnerable to DNA repair inhibition. Previous results from the Harris lab have identified UNG2, DNA uracil glycosylase 2 (UNG2), initiator of the base excision repair pathway, as synthetic lethal pair with A3B. The genetic disruption of UNG2 combined with high expression of A3B, causes cell death. This provides the rational to hypothesize that also other DNA repair proteins could be putative synthetic lethal pairs with A3B, when its expression and activity are high. To test this hypothesis, CRISPR guide RNA library targeting 237 DNA damage repair and response genes was used in doxycycline-inducible TREX-293-A3Bi-eGFP cell line. Cells expressing or not A3B were harvested for DNA extraction and sequencing at different time points. Comparison of guide RNA abundance between doxycycline and H2O treated cells revealed the dropout guides that disrupt genes and create putative synthetic lethal combinations with A3B. The screen design and overall results will be presented Citation Format: Bojana Stefanovska, Kevin Lin, Benjamin Troness, Chad Myers, Reuben Harris. Targeted CRISPR screen to identify synthetic lethal combinations between APOBEC3B and DNA repair [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-17-01.
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Vázquez, Nancy, Hana Schmeisser, Michael A. Dolan, Joseph Bekisz, Kathryn C. Zoon, and Sharon M. Wahl. "Structural variants of IFNα preferentially promote antiviral functions." Blood 118, no. 9 (September 1, 2011): 2567–77. http://dx.doi.org/10.1182/blood-2010-12-325027.
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AbstractIFNα, a cytokine with multiple functions in innate and adaptive immunity and a potent inhibitor of HIV, exerts antiviral activity, in part, by enhancing apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 (APOBEC3) family members. Although IFNα therapy is associated with reduced viral burden, this cytokine also mediates immune dysfunction and toxicities. Through detailed mapping of IFNα receptor binding sites, we generated IFNα hybrids and mutants and determined that structural changes in the C-helix alter the ability of IFN to limit retroviral activity. Selective IFNα constructs differentially block HIV replication and their directional magnitude of inhibition correlates with APOBEC3 levels. Importantly, certain mutants exhibited reduced toxicity as reflected by induced indoleamine 2,3-dioxygenase (IDO), suggesting discreet and shared intracellular signaling pathways. Defining IFN structure and function relative to APOBEC and other antiviral genes may enable design of novel IFN-related molecules preserving beneficial antiviral roles while minimizing negative effects.
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Kanabe, Belan O., Mehmet Ozaslan, Sherwan Ahmed Aziz, Mustafa S. Al-Attar, İbrahim Halil Kılıç, and Rozhgar A. Khailany. "Expression patterns of LncRNA-GAS5 and its target APOBEC3C gene through miR-103 in breast cancer patients." Cellular and Molecular Biology 67, no. 3 (November 25, 2021): 5–10. http://dx.doi.org/10.14715/cmb/2021.67.3.2.
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Early diagnosis of breast cancer can increase the survivability of the patients and the patient’s quality of life. There is growing evidence demonstrating the active role of LncRNA-GAS5 and miR-103 in cancer biology. APOBEC enzymes are important players in immunity and may contribute to carcinogenesis. Mutation and expression alteration in the APOBEC gene family was found to have a strong correlation with breast cancer risk. This study aimed to evaluate the expression level of lncRNA-GAS5 and its target APOBEC3C in women with breast cancer through expression evaluation of miR-103. Moreover, the interaction between lncRNA-GAS5 and miR-103 was studied. In the present study, forty paired tumor and normal samples classified based on breast cancer subtypes and clinical features of patients were analyzed using gene expression studies. Immunohistochemical analysis of the gene products was performed to classify tumors. The RNA samples were extracted from breast tissue. Real-time PCR was conducted for APOBEC3C and Lnc-RNA GAS5 expression. In addition, miR-103a miScript Primer Assay was utilized for the expression of miR-103-5p. It was revealed that the expression level of APOBEC3C and lncRNA-GAS5 were significantly down-regulated; however, the miRNA-103 expression level was significantly up-regulated. GAS5 expression was positively correlated with APOBEC3C expression and negatively correlated with miR-103 expression. In conclusion, we observed down-regulation of APOBEC3C and LncRNA-GAS5 and up-regulation of miRNA 103 in breast cancer patients. The expression of GAS5 may provide a new potential treatment target for breast cancer. To clarify the role of these molecules in the cellular signaling pathways, further studies are required.
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Zotova, Irina, Elena Stepchenkova, and Youri Pavlov. "Contribution of cytosine desaminases of AID/APOBEC family to carcinogenesis." Biological Communications 64, no. 2 (2019): 110–23. http://dx.doi.org/10.21638/spbu03.2019.203.
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Salter, Jason D., Ryan P. Bennett, and Harold C. Smith. "The APOBEC Protein Family: United by Structure, Divergent in Function." Trends in Biochemical Sciences 41, no. 7 (July 2016): 578–94. http://dx.doi.org/10.1016/j.tibs.2016.05.001.
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Turelli, Priscilla, Alexandra Liagre-Quazzola, Bastien Mangeat, Sonia Verp, Stephanie Jost, and Didier Trono. "APOBEC3-Independent Interferon-Induced Viral Clearance in Hepatitis B Virus Transgenic Mice." Journal of Virology 82, no. 13 (April 23, 2008): 6585–90. http://dx.doi.org/10.1128/jvi.00216-08.
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ABSTRACT Interferon (IFN) has been part of the standard treatment of chronic hepatitis B infection for more than 2 decades, yet the mechanism of action of this antiviral remains poorly understood. It was recently observed that members of the human APOBEC family of cytidine deaminases endowed with anti-hepatitis B virus (HBV) activity are upregulated by type I and II IFNs. However, we demonstrated that, in tissue culture, these cellular enzymes are not essential effectors of the anti-HBV action of these cytokines. Here, we show that murine APOBEC3 (muA3) can also block HBV replication. While expressed at low levels in the mouse liver at baseline, muA3 is upregulated upon IFN induction. However, in HBV-transgenic muA3 knockout mice, IFN induction blocked HBV DNA production as efficiently as in control HBV-transgenic muA3-competent animals. We conclude that APOBEC3 is not an essential mediator of the IFN-mediated inhibition of HBV in vivo.
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Rogozin, Igor B., Malay K. Basu, I. King Jordan, Youri I. Pavlov, and Eugene V. Koonin. "APOBEC4, a New Member of the AID/APOBEC Family of Polynucleotide (Deoxy)Cytidine Deaminases Predicted by Computational Analysis." Cell Cycle 4, no. 9 (July 6, 2005): 1281–85. http://dx.doi.org/10.4161/cc.4.9.1994.
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Anderson, Brett D., and Reuben S. Harris. "Transcriptional regulation of APOBEC3 antiviral immunity through the CBF-β/RUNX axis." Science Advances 1, no. 8 (September 2015): e1500296. http://dx.doi.org/10.1126/sciadv.1500296.
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A diverse set of innate immune mechanisms protects cells from viral infections. The APOBEC3 family of DNA cytosine deaminases is an integral part of these defenses. For instance, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H would have the potential to destroy HIV-1 complementary DNA replication intermediates if not for neutralization by a proteasomal degradation mechanism directed by the viral protein Vif. At the core of this complex, Vif heterodimerizes with the transcription cofactor CBF-β, which results in fewer transcription complexes between CBF-β and its normal RUNX partners. Recent studies have shown that the Vif/CBF-β interaction is specific to the primate lentiviruses HIV-1 and SIV (simian immunodeficiency virus), although related nonprimate lentiviruses still require a Vif-dependent mechanism for protection from host species’ APOBEC3 enzymes. We provide a molecular explanation for this evolutionary conundrum by showing that CBF-β is required for expression of the aforementioned HIV-1–restrictive APOBEC3 gene repertoire. Knockdown and knockout studies demonstrate that CBF-β is required for APOBEC3 mRNA expression in the nonpermissive T cell line H9 and in primary CD4+ T lymphocytes. Complementation experiments using CBF-β separation-of-function alleles show that the interaction with RUNX transcription factors is required for APOBEC3 transcriptional regulation. Accordingly, the infectivity of Vif-deficient HIV-1 increases in cells lacking CBF-β, demonstrating the importance of CBF-β/RUNX–mediated transcription in establishing the APOBEC3 antiviral state. These findings demonstrate a major layer of APOBEC3 gene regulation in lymphocytes and suggest that primate lentiviruses evolved to hijack CBF-β in order to simultaneously suppress this potent antiviral defense system at both transcriptional and posttranslational levels.