Articles de revues : « Deaminases »

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Rogozin, Igor, Abiel Roche-Lima, Artem Lada, Frida Belinky, Ivan Sidorenko, Galina Glazko, Vladimir Babenko, David Cooper et Youri Pavlov. « Nucleotide Weight Matrices Reveal Ubiquitous Mutational Footprints of AID/APOBEC Deaminases in Human Cancer Genomes ». Cancers 11, n^o 2 (12 février 2019) : 211. http://dx.doi.org/10.3390/cancers11020211.

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Cancer genomes accumulate nucleotide sequence variations that number in the tens of thousands per genome. A prominent fraction of these mutations is thought to arise as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases. These enzymes, collectively called activation induced deaminase (AID)/APOBECs, deaminate cytosines located within defined DNA sequence contexts. The resulting changes of the original C:G pair in these contexts (mutational signatures) provide indirect evidence for the participation of specific cytosine deaminases in a given cancer type. The conventional method used for the analysis of mutable motifs is the consensus approach. Here, for the first time, we have adopted the frequently used weight matrix (sequence profile) approach for the analysis of mutagenesis and provide evidence for this method being a more precise descriptor of mutations than the sequence consensus approach. We confirm that while mutational footprints of APOBEC1, APOBEC3A, APOBEC3B, and APOBEC3G are prominent in many cancers, mutable motifs characteristic of the action of the humoral immune response somatic hypermutation enzyme, AID, are the most widespread feature of somatic mutation spectra attributable to deaminases in cancer genomes. Overall, the weight matrix approach reveals that somatic mutations are significantly associated with at least one AID/APOBEC mutable motif in all studied cancers.

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Seffernick, Jennifer L., Anthony G. Dodge, Michael J. Sadowsky, John A. Bumpus et Lawrence P. Wackett. « Bacterial Ammeline Metabolism via Guanine Deaminase ». Journal of Bacteriology 192, n^o 4 (18 décembre 2009) : 1106–12. http://dx.doi.org/10.1128/jb.01243-09.

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ABSTRACT Melamine toxicity in mammals has been attributed to the blockage of kidney tubules by insoluble complexes of melamine with cyanuric acid or uric acid. Bacteria metabolize melamine via three consecutive deamination reactions to generate cyanuric acid. The second deamination reaction, in which ammeline is the substrate, is common to many bacteria, but the genes and enzymes responsible have not been previously identified. Here, we combined bioinformatics and experimental data to identify guanine deaminase as the enzyme responsible for this biotransformation. The ammeline degradation phenotype was demonstrated in wild-type Escherichia coli and Pseudomonas strains, including E. coli K12 and Pseudomonas putida KT2440. Bioinformatics analysis of these and other genomes led to the hypothesis that the ammeline deaminating enzyme was guanine deaminase. An E. coli guanine deaminase deletion mutant was deficient in ammeline deaminase activity, supporting the role of guanine deaminase in this reaction. Two guanine deaminases from disparate sources (Bradyrhizobium japonicum USDA 110 and Homo sapiens) that had available X-ray structures were purified to homogeneity and shown to catalyze ammeline deamination at rates sufficient to support bacterial growth on ammeline as a sole nitrogen source. In silico models of guanine deaminase active sites showed that ammeline could bind to guanine deaminase in a similar orientation to guanine, with a favorable docking score. Other members of the amidohydrolase superfamily that are not guanine deaminases were assayed in vitro, and none had substantial ammeline deaminase activity. The present study indicated that widespread guanine deaminases have a promiscuous activity allowing them to catalyze a key reaction in the bacterial transformation of melamine to cyanuric acid and potentially contribute to the toxicity of melamine.

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Vasudevan, Ananda Ayyappan Jaguva, Sander H. J. Smits, Astrid Höppner, Dieter Häussinger, Bernd W. Koenig et Carsten Münk. « Structural features of antiviral DNA cytidine deaminases ». Biological Chemistry 394, n^o 11 (1 novembre 2013) : 1357–70. http://dx.doi.org/10.1515/hsz-2013-0165.

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Abstract The APOBEC3 (A3) family of cytidine deaminases plays a vital role for innate defense against retroviruses. Lentiviruses such as HIV-1 evolved the Vif protein that triggers A3 protein degradation. There are seven A3 proteins, A3A-A3H, found in humans. All A3 proteins can deaminate cytidines to uridines in single-stranded DNA (ssDNA), generated during viral reverse transcription. A3 proteins have either one or two cytidine deaminase domains (CD). The CDs coordinate a zinc ion, and their amino acid specificity classifies the A3s into A3Z1, A3Z2, and A3Z3. A3 proteins occur as monomers, dimers, and large oligomeric complexes. Studies on the nature of A3 oligomerization, as well as the mode of interaction of A3s with RNA and ssDNA are partially controversial. High-resolution structures of the catalytic CD2 of A3G and A3F as well as of the single CD proteins A3A and A3C have been published recently. The NMR and X-ray crystal structures show globular proteins with six α-helices and five β sheets arranged in a characteristic motif (α1-β1-β2/2′-α2-β3-α3-β4-α4-β5-α5-α6). However, the detailed arrangement and extension of individual structure elements and their relevance for A3 complex formation and activity remains a matter of debate and will be highlighted in this review.

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Teperek-Tkacz, Marta, Vincent Pasque, George Gentsch et Anne C. Ferguson-Smith. « Epigenetic reprogramming : is deamination key to active DNA demethylation ? » REPRODUCTION 142, n^o 5 (novembre 2011) : 621–32. http://dx.doi.org/10.1530/rep-11-0148.

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DNA demethylation processes are important for reproduction, being central in epigenetic reprogramming during embryonic and germ cell development. While the enzymes methylating DNA have been known for many years, identification of factors capable of mediating active DNA demethylation has been challenging. Recent findings suggest that cytidine deaminases may be key players in active DNA demethylation. One of the most investigated candidates is activation-induced cytidine deaminase (AID), best known for its role in generating secondary antibody diversity in B cells. We evaluate evidence for cytidine deaminases in DNA demethylation pathways in vertebrates and discuss possible models for their targeting and activity regulation. These findings are also considered along with alternative demethylation pathways involving hydroxymethylation.

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Roth, E. Jr, N. Ogasawara et S. Schulman. « The deamination of adenosine and adenosine monophosphate in Plasmodium falciparum-infected human erythrocytes : in vitro use of 2'deoxycoformycin and AMP deaminase-deficient red cells ». Blood 74, n^o 3 (15 août 1989) : 1121–25. http://dx.doi.org/10.1182/blood.v74.3.1121.1121.

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Abstract The role of enzymatic deamination of adenosine monophosphate (AMP) and adenosine in the in vitro growth of the malaria parasite Plasmodium falciparum was investigated by means of human red cells deficient in AMP deaminase to which the adenosine deaminase inhibitor 2′- deoxycoformycin was added. Malaria parasites grew normally in red cells lacking one or both of these enzyme activities. As a further probe of adenosine triphosphate (ATP) catabolism, both infected and uninfected RBCs were incubated with NaF (with and without 2′-deoxycoformycin) and the purine nucleotide/nucleoside content was analyzed by high- performance liquid chromatography (HPLC). Uninfected RBCs lacking either AMP or adenosine deaminase were able to bypass the enzyme block and degrade ATP to hypoxanthine. Uninfected RBCs with both deaminases blocked were unable to produce significant quantities of hypoxanthine. On the other hand, infected RBCs were able to bypass blockade of both deaminases and produce hypoxanthine and adenosine. These findings establish that deamination of adenosine and/or AMP are not essential for plasmodial growth. However, further work will be required to elucidate the pathways that permit the parasites to bypass these catabolic steps.

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Roth, E. Jr, N. Ogasawara et S. Schulman. « The deamination of adenosine and adenosine monophosphate in Plasmodium falciparum-infected human erythrocytes : in vitro use of 2'deoxycoformycin and AMP deaminase-deficient red cells ». Blood 74, n^o 3 (15 août 1989) : 1121–25. http://dx.doi.org/10.1182/blood.v74.3.1121.bloodjournal7431121.

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The role of enzymatic deamination of adenosine monophosphate (AMP) and adenosine in the in vitro growth of the malaria parasite Plasmodium falciparum was investigated by means of human red cells deficient in AMP deaminase to which the adenosine deaminase inhibitor 2′- deoxycoformycin was added. Malaria parasites grew normally in red cells lacking one or both of these enzyme activities. As a further probe of adenosine triphosphate (ATP) catabolism, both infected and uninfected RBCs were incubated with NaF (with and without 2′-deoxycoformycin) and the purine nucleotide/nucleoside content was analyzed by high- performance liquid chromatography (HPLC). Uninfected RBCs lacking either AMP or adenosine deaminase were able to bypass the enzyme block and degrade ATP to hypoxanthine. Uninfected RBCs with both deaminases blocked were unable to produce significant quantities of hypoxanthine. On the other hand, infected RBCs were able to bypass blockade of both deaminases and produce hypoxanthine and adenosine. These findings establish that deamination of adenosine and/or AMP are not essential for plasmodial growth. However, further work will be required to elucidate the pathways that permit the parasites to bypass these catabolic steps.

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Jost, Stéphanie, Priscilla Turelli, Bastien Mangeat, Ulrike Protzer et Didier Trono. « Induction of Antiviral Cytidine Deaminases Does Not Explain the Inhibition of Hepatitis B Virus Replication by Interferons ». Journal of Virology 81, n^o 19 (25 juillet 2007) : 10588–96. http://dx.doi.org/10.1128/jvi.02489-06.

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ABSTRACT Interferons (IFNs) play a major role in the control of hepatitis B virus (HBV), whether as endogenous cytokines limiting the spread of the virus during the acute phase of the infection or as drugs for the treatment of its chronic phase. However, the mechanism by which IFNs inhibit HBV replication has so far remained elusive. Here, we show that type I and II IFN treatment of human hepatocytes induces the production of APOBEC3G (A3G) and, to a lesser extent, that of APOBEC3F (A3F) and APOBEC3B (A3B) but not that of two other cytidine deaminases also endowed with anti-HBV activity, activation-induced cytidine deaminase (AID), and APOBEC1. Most importantly, we reveal that blocking A3B, A3F, and A3G by combining RNA interference and the virion infectivity factor (Vif) protein of human immunodeficiency virus does not abrogate the inhibitory effect of IFNs on HBV. We conclude that these cytidine deaminases are not essential effectors of IFN in its action against this pathogen.

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Liu, Lei, Jian-Feng Wu, Ying-Fei Ma, Sheng-Yue Wang, Guo-Ping Zhao et Shuang-Jiang Liu. « A Novel Deaminase Involved in Chloronitrobenzene and Nitrobenzene Degradation with Comamonas sp. Strain CNB-1 ». Journal of Bacteriology 189, n^o 7 (26 janvier 2007) : 2677–82. http://dx.doi.org/10.1128/jb.01762-06.

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ABSTRACT Comamonas sp. strain CNB-1 degrades nitrobenzene and chloronitrobenzene via the intermediates 2-aminomuconate and 2-amino-5-chloromuconate, respectively. Deamination of these two compounds results in the release of ammonia, which is used as a source of nitrogen for bacterial growth. In this study, a novel deaminase was purified from Comamonas strain CNB-1, and the gene (cnbZ) encoding this enzyme was cloned. The N-terminal sequence and peptide fingerprints of this deaminase were determined, and BLAST searches revealed no match with significant similarity to any functionally characterized proteins. The purified deaminase is a monomer (30 kDa), and its V max values for 2-aminomuconate and 2-amino-5-chloromuconate were 147 μmol·min−1·mg−1 and 196 μmol·min−1·mg−1, respectively. Its catalytic products from 2-aminomuconate and 2-amino-5-chloromuconate were 2-hydroxymuconate and 2-hydroxy-5-chloromuconate, respectively, which are different from those previously reported for the deaminases of Pseudomonas species. In the catalytic mechanism proposed, the α-carbon and nitrogen atoms (of both 2-aminomuconate and 2-amino-5-chloromuconate) were simultaneously attacked by a hydroxyl group and a proton, respectively. Homologs of cnbZ were identified in the genomes of Bradyrhizobium japonicum, Rhodopseudomonas palustris, and Roseiflexus sp. strain RS-1; these genes were previously annotated as encoding hypothetical proteins of unknown function. It is concluded that CnbZ represents a novel enzyme that deaminates xenobiotic compounds and/or α-amino acids.

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Mahieux, Renaud, Rodolphe Suspène, Frédéric Delebecque, Michel Henry, Olivier Schwartz, Simon Wain-Hobson et Jean-Pierre Vartanian. « Extensive editing of a small fraction of human T-cell leukemia virus type 1 genomes by four APOBEC3 cytidine deaminases ». Journal of General Virology 86, n^o 9 (1 septembre 2005) : 2489–94. http://dx.doi.org/10.1099/vir.0.80973-0.

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In the absence of the human immunodeficiency virus type 1 (HIV-1) Vif protein, the host-cell cytidine deaminases APOBEC3F and -3G are co-packaged along with virion RNA. Upon infection of target cells, nascent single-stranded DNA can be edited extensively, invariably giving rise to defective genomes called G→A hypermutants. Although human T-cell leukemia virus type 1 (HTLV-1) replicates in the same cell type as HIV-1, it was shown here that HTLV-1 is relatively resistant to the antiviral effects mediated by human APOBEC3B, -3C, -3F and -3G. Nonetheless, a small percentage of genomes (0·1<f<5 %) were edited extensively: up to 97 % of cytidine targets were deaminated. In contrast, hypermutated HTLV-1 genomes were not identified in peripheral blood mononuclear cell DNA from ten patients with non-malignant HTLV-1 infection. Thus, although HTLV-1 DNA can indeed be edited by at least four APOBEC3 cytidine deaminases in vitro, they are conspicuously absent in vivo.

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Morgan, Hugh D., Wendy Dean, Heather A. Coker, Wolf Reik et Svend K. Petersen-Mahrt. « Activation-induced Cytidine Deaminase Deaminates 5-Methylcytosine in DNA and Is Expressed in Pluripotent Tissues ». Journal of Biological Chemistry 279, n^o 50 (24 septembre 2004) : 52353–60. http://dx.doi.org/10.1074/jbc.m407695200.

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DNA deaminases of the Aid/Apobec family convert cytosine into uracil and play key roles in acquired and innate immunity. The epigenetic modification by methylation of cytosine in CpG dinucleotides is also mutagenic, but this is thought to occur by spontaneous deamination. Here we show that Aid and Apobec1 are 5-methylcytosine deaminases resulting in a thymine base opposite a guanine. Their action can thus lead to C → T transition mutations in methylated DNA, or in conjunction with repair of the T:G mismatch, to demethylation. TheAidandApobec1genes are located in a cluster of pluripotency genes includingNanogandStellaand are co-expressed with these genes in oocytes, embryonic germ cells, and embryonic stem cells. These results suggest that Aid and perhaps some of its family members may have roles in epigenetic reprogramming and cell plasticity. Transition in CpG dinucleotides is the most frequent mutation in human genetic diseases, and sequence context analysis of CpG transitions in the APC tumor suppressor gene suggests that DNA deaminases may play a significant role in tumor etiology.

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Brezgin, Sergey, Anastasiya Kostyusheva, Natalia Ponomareva, Viktoriia Volia, Irina Goptar, Anastasiya Nikiforova, Igor Shilovskiy, Valery Smirnov, Dmitry Kostyushev et Vladimir Chulanov. « Clearing of Foreign Episomal DNA from Human Cells by CRISPRa-Mediated Activation of Cytidine Deaminases ». International Journal of Molecular Sciences 21, n^o 18 (18 septembre 2020) : 6865. http://dx.doi.org/10.3390/ijms21186865.

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Restriction of foreign DNA is a fundamental defense mechanism required for maintaining genomic stability and proper function of mammalian cells. APOBEC cytidine deaminases are crucial effector molecules involved in clearing pathogenic DNA of viruses and other microorganisms and improperly localized self-DNA (DNA leakages). Mastering the expression of APOBEC provides the crucial means both for developing novel therapeutic approaches for combating infectious and non-infectious diseases and for numerous research purposes. In this study, we report successful application of a CRISPRa approach to effectively and specifically overexpress APOBEC3A and APOBEC3B deaminases and describe their effects on episomal and integrated foreign DNA. This method increased target gene transcription by >6–50-fold in HEK293T cells. Furthermore, CRISPRa-mediated activation of APOBEC3A/APOBEC3B suppressed episomal but not integrated foreign DNA. Episomal GC-rich DNA was rapidly destabilized and destroyed by CRISPRa-induced APOBEC3A/APOBEC3B, while the remaining DNA templates harbored frequent deaminated nucleotides. To conclude, the CRISPRa approach could be readily utilized for manipulating innate immunity and investigating the effects of the key effector molecules on foreign nucleic acids.

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Delviks-Frankenberry, Krista A., Belete A. Desimmie et Vinay K. Pathak. « Structural Insights into APOBEC3-Mediated Lentiviral Restriction ». Viruses 12, n^o 6 (27 mai 2020) : 587. http://dx.doi.org/10.3390/v12060587.

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Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is continuously evolving to expand the repertoire of restriction factors and one such family of intrinsic restriction factors is the APOBEC3 (A3) family of cytidine deaminases. The coordinated expression of seven members of the A3 family of cytidine deaminases provides intrinsic immunity against numerous foreign infectious agents and protects the host from exogenous retroviruses and endogenous retroelements. Four members of the A3 proteins—A3G, A3F, A3H, and A3D—restrict HIV-1 in the absence of virion infectivity factor (Vif); their incorporation into progeny virions is a prerequisite for cytidine deaminase-dependent and -independent activities that inhibit viral replication in the host target cell. HIV-1 encodes Vif, an accessory protein that antagonizes A3 proteins by targeting them for polyubiquitination and subsequent proteasomal degradation in the virus producing cells. In this review, we summarize our current understanding of the role of human A3 proteins as barriers against HIV-1 infection, how Vif overcomes their antiviral activity, and highlight recent structural and functional insights into A3-mediated restriction of lentiviruses.

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Bitra, Aruna, et Ruchi Anand. « Structure based protein engineering to confer selectivity of guanine deaminase ». Acta Crystallographica Section A Foundations and Advances 70, a1 (5 août 2014) : C437. http://dx.doi.org/10.1107/s205327331409562x.

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Guanine deaminases (GDs) are important enzymes involved in both purine metabolism and nucleotide anabolism pathways. Here we present the molecular and catalytic mechanism of NE0047 and use the information obtained to engineer specific enzyme activities. NE0047 from Nitrosomonas europaea was found to be a high fidelity guanine deaminase (catalytic efficiency of 1.2 × 105 M–1 s–1). However; it exhibited secondary activity towards the structurally non-analogous triazine based compound ammeline. The X-ray structure of NE0047 in the presence of the substrate analogue 8-azaguanine help establish that the enzyme exists as a biological dimer and both the proper closure of the C-terminal loop and cross talk via the dimeric interface is crucial for conferring catalytic activity. It was further ascertained that the highly conserved active site residues Glu79 and Glu143 facilitate the deamination reaction by serving as proton shuttles. Moreover, to understand the structural basis of dual substrate specificity, X-ray structures of NE0047 in complex with a series of nucleobase analogs, nucleosides and substrate ammeline were determined. The crystal structures demonstrated that any substitutions in the parent substrates results in the rearrangement of the ligand in a catalytically unfavorable orientation and also impede the closure of catalytically important loop, thereby abrogating activity. However, ammeline was able to adopt a catalytically favorable orientation which, also allowed for proper loop closure. Based on the above knowledge of the crystal structures and the catalytic mechanism, the active site was subsequently engineered to fine-tune NE0047 activity. The mutated versions of the enzyme were designed so that they can function either exclusively as a GD or serve as specific ammeline deaminases. For example, mutations in the active site E143D and N66A confer the enzyme to be an unambiguous GD with no secondary activity towards ammeline. On the other hand, the N66Q mutant of NE0047 only deaminates ammeline. Additionally, a series of crystal structures of the mutant versions were solved that shed light on the structural basis of this differential selectivity.

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Conticello, Silvestro G., Marc-Andre Langlois et Michael S. Neuberger. « Insights into DNA deaminases ». Nature Structural & ; Molecular Biology 14, n^o 1 (janvier 2007) : 7–9. http://dx.doi.org/10.1038/nsmb0107-7.

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Hakata, Yoshiyuki, et Masaaki Miyazawa. « Deaminase-Independent Mode of Antiretroviral Action in Human and Mouse APOBEC3 Proteins ». Microorganisms 8, n^o 12 (12 décembre 2020) : 1976. http://dx.doi.org/10.3390/microorganisms8121976.

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Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) proteins (APOBEC3s) are deaminases that convert cytosines to uracils predominantly on a single-stranded DNA, and function as intrinsic restriction factors in the innate immune system to suppress replication of viruses (including retroviruses) and movement of retrotransposons. Enzymatic activity is supposed to be essential for the APOBEC3 antiviral function. However, it is not the only way that APOBEC3s exert their biological function. Since the discovery of human APOBEC3G as a restriction factor for HIV-1, the deaminase-independent mode of action has been observed. At present, it is apparent that both the deaminase-dependent and -independent pathways are tightly involved not only in combating viruses but also in human tumorigenesis. Although the deaminase-dependent pathway has been extensively characterized so far, understanding of the deaminase-independent pathway remains immature. Here, we review existing knowledge regarding the deaminase-independent antiretroviral functions of APOBEC3s and their molecular mechanisms. We also discuss the possible unidentified molecular mechanism for the deaminase-independent antiretroviral function mediated by mouse APOBEC3.

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Keegan, Liam P., André P. Gerber, Jim Brindle, Ronny Leemans, Angela Gallo, Walter Keller et Mary A. O'Connell. « The Properties of a tRNA-Specific Adenosine Deaminase from Drosophila melanogaster Support an Evolutionary Link between Pre-mRNA Editing and tRNA Modification ». Molecular and Cellular Biology 20, n^o 3 (1 février 2000) : 825–33. http://dx.doi.org/10.1128/mcb.20.3.825-833.2000.

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ABSTRACT Pre-mRNA editing involving the conversion of adenosine to inosine is mediated by adenosine deaminases that act on RNA (ADAR1 and ADAR2). ADARs contain multiple double-stranded RNA(dsRNA)-binding domains in addition to an adenosine deaminase domain. An adenosine deaminase acting on tRNAs, scTad1p (also known as scADAT1), cloned fromSaccharomyces cerevisiae has a deaminase domain related to the ADARs but lacks dsRNA-binding domains. We have identified a gene homologous to scADAT1 in the region of Drosophila melanogaster Adh chromosome II. Recombinant Drosophila ADAT1 (dADAT1) has been expressed in the yeast Pichia pastorisand purified. The enzyme has no activity on dsRNA substrates but is a tRNA deaminase with specificity for adenosine 37 of insect alanine tRNA. dADAT1 shows greater similarity to vertebrate ADARs than to yeast Tad1p, supporting the hypothesis of a common evolutionary origin for ADARs and ADATs. dAdat1 transcripts are maternally supplied in the egg. Zygotic expression is widespread initially and later concentrates in the central nervous system.

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Bonvin, Marianne, et Jobst Greeve. « Effects of point mutations in the cytidine deaminase domains of APOBEC3B on replication and hypermutation of hepatitis B virus in vitro ». Journal of General Virology 88, n^o 12 (1 décembre 2007) : 3270–74. http://dx.doi.org/10.1099/vir.0.83149-0.

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APOBEC3 cytidine deaminases hypermutate hepatitis B virus (HBV) and inhibit its replication in vitro. Whether this inhibition is due to the generation of hypermutations or to an alternative mechanism is controversial. A series of APOBEC3B (A3B) point mutants was analysed in vitro for hypermutational activity on HBV DNA and for inhibitory effects on HBV replication. Point mutations inactivating the carboxy-terminal deaminase domain abolished the hypermutational activity and reduced the inhibitory activity on HBV replication to approximately 40 %. In contrast, the point mutation H66R, inactivating the amino-terminal deaminase domain, did not affect hypermutations, but reduced the inhibition activity to 63 %, whilst the mutant C97S had no effect in either assay. Thus, only the carboxy-terminal deaminase domain of A3B catalyses cytidine deaminations leading to HBV hypermutations, but induction of hypermutations is not sufficient for full inhibition of HBV replication, for which both domains of A3B must be intact.

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Hernández-Camarero, Pablo, Elena López-Ruiz, Juan Antonio Marchal et Macarena Perán. « Unifying Different Cancer Theories in a Unique Tumour Model : Chronic Inflammation and Deaminases as Meeting Points ». International Journal of Molecular Sciences 23, n^o 15 (5 août 2022) : 8720. http://dx.doi.org/10.3390/ijms23158720.

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The increase in cancer incidences shows that there is a need to better understand tumour heterogeneity to achieve efficient treatments. Interestingly, there are several common features among almost all types of cancers, with chronic inflammation induction and deaminase dysfunctions singled out. Deaminases are a family of enzymes with nucleotide-editing capacity, which are classified into two main groups: DNA-based and RNA-based. Remarkably, a close relationship between inflammation and the dysregulation of these molecules has been widely documented, which may explain the characteristic intratumor heterogeneity, both at DNA and transcriptional levels. Indeed, heterogeneity in cancer makes it difficult to establish a unique tumour progression model. Currently, there are three main cancer models—stochastic, hierarchic, and dynamic—although there is no consensus on which one better resembles cancer biology because they are usually overly simplified. Here, to accurately explain tumour progression, we propose interactions among chronic inflammation, deaminases dysregulation, intratumor genetic heterogeneity, cancer phenotypic plasticity, and even the previously proposed appearance of cancer stem-like cell populations in the edges of advanced solid tumour masses (instead of being the cells of origin of primary malignancies). The new tumour development model proposed in this study does not contradict previously accepted models and it may open up a window to interesting therapeutic approaches.

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Spychała, J., K. Kaletha et W. Makarewicz. « Developmental changes of chicken liver AMP deaminase ». Biochemical Journal 231, n^o 2 (15 octobre 1985) : 329–33. http://dx.doi.org/10.1042/bj2310329.

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The AMP deaminase activity measured in crude chicken liver extract did not change significantly during development. The livers of 10- and 14-day chick embryos, 1-day, 5-, 10- and 16-week-old chickens and adult hens were examined for the existence of multiple forms of AMP deaminase. Phosphocellulose column chromatography revealed the existence of two peaks of enzyme activity in the liver of 10- and 16-week-old chickens and adult hens. Kinetic studies with the preparations of AMP deaminase revealed sigmoid-shaped substrate-saturation curves at all developmental stages and hyperbolic-shaped saturation curves for the enzyme form appearing in 10-week-old chickens. All AMP deaminases investigated were susceptible to activation by ATP and inhibition by Pi. Kinetic and regulatory properties as well as pH optima of all the enzyme preparations tested indicate that AMP deaminase isolated from the embryos and from 1-day-old chicks was similar to the form I isolated from adult hens and differed significantly from the form II of this enzyme.

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Miyagi, Eri, Charles R. Brown, Sandrine Opi, Mohammad Khan, Ritu Goila-Gaur, Sandra Kao, Robert C. Walker, Vanessa Hirsch et Klaus Strebel. « Stably Expressed APOBEC3F Has Negligible Antiviral Activity ». Journal of Virology 84, n^o 21 (11 août 2010) : 11067–75. http://dx.doi.org/10.1128/jvi.01249-10.

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ABSTRACT APOBEC3F (A3F) is a member of the family of cytidine deaminases that is often coexpressed with APOBEC3G (A3G) in cells susceptible to HIV infection. A3F has been shown to have strong antiviral activity in transient-expression studies, and together with A3G, it is considered the most potent cytidine deaminase targeting HIV. Previous analyses suggested that the antiviral properties of A3F can be dissociated from its catalytic deaminase activity. We were able to confirm the deaminase-independent antiviral activity of exogenously expressed A3F; however, we also noted that exogenous expression was associated with very high A3F mRNA and protein levels. In analogy to our previous study of A3G, we produced stable HeLa cell lines constitutively expressing wild-type or deaminase-defective A3F at levels that were more in line with the levels of endogenous A3F in H9 cells. A3F expressed in stable HeLa cells was packaged into Vif-deficient viral particles with an efficiency similar to that of A3G and was properly targeted to the viral nucleoprotein complex. Surprisingly, however, neither wild-type nor deaminase-defective A3F inhibited HIV-1 infectivity. These results imply that the antiviral activity of endogenous A3F is negligible compared to that of A3G.

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Navaratnam, Naveenan, et Rizwan Sarwar. « An Overview of Cytidine Deaminases ». International Journal of Hematology 83, n^o 3 (1 avril 2006) : 195–200. http://dx.doi.org/10.1532/ijh97.06032.

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Rebhandl, Stefan, Michael Huemer, Richard Greil et Roland Geisberger. « AID/APOBEC deaminases and cancer ». Oncoscience 2, n^o 4 (28 avril 2015) : 320–33. http://dx.doi.org/10.18632/oncoscience.155.

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Fritz, E. L., et F. N. Papavasiliou. « Cytidine deaminases : AIDing DNA demethylation ? » Genes & ; Development 24, n^o 19 (1 octobre 2010) : 2107–14. http://dx.doi.org/10.1101/gad.1963010.

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Buchumenski, Ilana, Shalom Hillel Roth, Eli Kopel, Efrat Katsman, Ariel Feiglin, Erez Y. Levanon et Eli Eisenberg. « Global quantification exposes abundant low-level off-target activity by base editors ». Genome Research 31, n^o 12 (19 octobre 2021) : 2354–61. http://dx.doi.org/10.1101/gr.275770.121.

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Base editors are dedicated engineered deaminases that enable directed conversion of specific bases in the genome or transcriptome in a precise and efficient manner, and hold promise for correcting pathogenic mutations. A major concern limiting application of this powerful approach is the issue of off-target edits. Several recent studies have shown substantial off-target RNA activity induced by base editors and demonstrated that off-target mutations may be suppressed by improved deaminases versions or optimized guide RNAs. Here, we describe a new class of off-target events that are invisible to the established methods for detection of genomic variations and were thus far overlooked. We show that nonspecific, seemingly stochastic, off-target events affect a large number of sites throughout the genome or the transcriptome, and account for the majority of off-target activity. We develop and employ a different, complementary approach that is sensitive to the stochastic off-target activity and use it to quantify the abundant off-target RNA mutations due to current, optimized deaminase editors. We provide a computational tool to quantify global off-target activity, which can be used to optimize future base editors. Engineered base editors enable directed manipulation of the genome or transcriptome at single-base resolution. We believe that implementation of this computational approach would facilitate design of more specific base editors.

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Bavelloni, Alberto, Enrico Focaccia, Manuela Piazzi, Mirco Raffini, Valeriana Cesarini, Sara Tomaselli, Arianna Orsini et al. « AKT‐dependent phosphorylation of the adenosine deaminases ADAR‐1 and ‐2 inhibits deaminase activity ». FASEB Journal 33, n^o 8 (16 mai 2019) : 9044–61. http://dx.doi.org/10.1096/fj.201800490rr.

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Schatz, David G. « DNA deaminases converge on adaptive immunity ». Nature Immunology 8, n^o 6 (juin 2007) : 551–53. http://dx.doi.org/10.1038/ni0607-551.

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Spychałek, Józef, Jarosław Marszałek et Ewa Kucharczyk. « AMP deaminases of rat small intestine ». Biochimica et Biophysica Acta (BBA) - General Subjects 880, n^o 2-3 (février 1986) : 123–30. http://dx.doi.org/10.1016/0304-4165(86)90071-1.

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Di Giorgio, Salvatore, Filippo Martignano, Maria Gabriella Torcia, Giorgio Mattiuz et Silvestro G. Conticello. « Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2 ». Science Advances 6, n^o 25 (18 mai 2020) : eabb5813. http://dx.doi.org/10.1126/sciadv.abb5813.

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The COVID-19 outbreak has become a global health risk, and understanding the response of the host to the SARS-CoV-2 virus will help to combat the disease. RNA editing by host deaminases is an innate restriction process to counter virus infection, but it is not yet known whether this process operates against coronaviruses. Here, we analyze RNA sequences from bronchoalveolar lavage fluids obtained from coronavirus-infected patients. We identify nucleotide changes that may be signatures of RNA editing: adenosine-to-inosine changes from ADAR deaminases and cytosine-to-uracil changes from APOBEC deaminases. Mutational analysis of genomes from different strains of Coronaviridae from human hosts reveals mutational patterns consistent with those observed in the transcriptomic data. However, the reduced ADAR signature in these data raises the possibility that ADARs might be more effective than APOBECs in restricting viral propagation. Our results thus suggest that both APOBECs and ADARs are involved in coronavirus genome editing, a process that may shape the fate of both virus and patient.

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Niewiadomska, Anna Maria, Chunjuan Tian, Lindi Tan, Tao Wang, Phuong Thi Nguyen Sarkis et Xiao-Fang Yu. « Differential Inhibition of Long Interspersed Element 1 by APOBEC3 Does Not Correlate with High-Molecular-Mass-Complex Formation or P-Body Association ». Journal of Virology 81, n^o 17 (20 juin 2006) : 9577–83. http://dx.doi.org/10.1128/jvi.02800-06.

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ABSTRACT The human cytidine deaminase APOBEC3G (A3G) and other APOBEC3 proteins exhibit differential inhibitory activities against diverse endogenous retroelements and retroviruses, including Vif-deficient human immunodeficiency virus type 1. The potential inhibitory activity of human APOBEC proteins against long interspersed element 1 (LINE-1) has not been fully evaluated. Here, we demonstrate inhibition of LINE-1 by multiple human APOBEC3 cytidine deaminases, including previously unreported activity for A3DE and A3G. More ancient members of APOBEC, cytidine deaminases AID and APOBEC2, had no detectable activity against LINE-1. A3A, which did not form high-molecular-mass (HMM) complexes and interacted poorly with P bodies, was the most potent inhibitor of LINE-1. A3A specifically recognizes LINE-1 RNA but not the other cellular RNAs tested. However, in the presence of LINE-1, A3A became associated with HMM complexes containing LINE-1 RNA. The ability of A3A to recognize LINE-1 RNA required its catalytic domain and was important for its LINE-1 suppression. Although the mechanism of LINE-1 restriction did not seem to involve DNA editing, A3A inhibited the accumulation of nascent LINE-1 DNA, suggesting interference with LINE-1 reverse transcription and/or integration or intracellular movement of LINE-1 ribonucleoprotein. Thus, association with P bodies or cellular HMM complexes could not predict the potency of APOBEC3 anti-LINE-1 activities. The catalytic domain of APOBEC3 proteins may be important for proper folding and target factors such as RNA or protein interaction in addition to cytidine deamination.

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Zhang, Wenyan, Juan Du, Kevin Yu, Tao Wang, Xiong Yong et Xiao-Fang Yu. « Association of Potent Human Antiviral Cytidine Deaminases with 7SL RNA and Viral RNP in HIV-1 Virions ». Journal of Virology 84, n^o 24 (6 octobre 2010) : 12903–13. http://dx.doi.org/10.1128/jvi.01632-10.

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ABSTRACT 7SL RNA promotes the formation of the signal recognition particle that targets secretory and membrane proteins to the endoplasmic reticulum. 7SL RNA is also selectively packaged by many retroviruses, including HIV-1. Here, we demonstrate that 7SL RNA is an integral component of the viral ribonucleoprotein (RNP) complex containing Gag, viral genomic RNA, and \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathbf{tRNA}_{3}^{Lys}\) \end{document} . Only the potent anti-HIV-1 cytidine deaminases can bind to 7SL RNA and target to HIV-1 RNP. A conserved motif in the amino-terminal region of A3G is important for 7SL RNA interaction. The weak anti-HIV-1 A3C did not interact with 7SL RNA and failed to target to viral RNPs, despite efficient virion packaging. However, a chimeric construct of A3C plus the 7SL-binding amino terminus of A3G did target to viral RNPs and showed enhanced anti-HIV-1 activity. 7SL RNA binding is a conserved feature of human anti-HIV-1 cytidine deaminases. Thus, potent anti-HIV-1 cytidine deaminases have evolved to possess a unique RNA-binding ability for precise HIV-1 targeting and viral inhibition.

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Wu, Jian-feng, Cheng-ying Jiang, Bao-jun Wang, Ying-fei Ma, Zhi-pei Liu et Shuang-jiang Liu. « Novel Partial Reductive Pathway for 4-Chloronitrobenzene and Nitrobenzene Degradation in Comamonas sp. Strain CNB-1 ». Applied and Environmental Microbiology 72, n^o 3 (mars 2006) : 1759–65. http://dx.doi.org/10.1128/aem.72.3.1759-1765.2006.

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ABSTRACT Comamonas sp. strain CNB-1 grows on 4-chloronitrobenzene (4-CNB) and nitrobenzene as sole carbon and nitrogen sources. In this study, two genetic segments, cnbB-orf2-cnbA and cnbR-orf1-cnbCaCbDEFGHI, located on a newly isolated plasmid, pCNB1 (ca. 89 kb), and involved in 4-CNB/nitrobenzene degradation, were characterized. Seven genes (cnbA, cnbB, cnbCa, cnbCb, cnbD, cnbG, and cnbH) were cloned and functionally expressed in recombinant Escherichia coli, and they were identified as encoding 4-CNB nitroreductase (CnbA), 1-hydroxylaminobenzene mutase (CnbB), 2-aminophenol 1,6-dioxygenase (CnbCab), 2-amino-5-chloromuconic semialdehyde dehydrogenase (CnbD), 2-hydroxy-5-chloromuconic acid (2H5CM) tautomerase, and 2-amino-5-chloromuconic acid (2A5CM) deaminase (CnbH). In particular, the 2A5CM deaminase showed significant identities (31 to 38%) to subunit A of Asp-tRNAAsn/Glu-tRNAGln amidotransferase and not to the previously identified deaminases for nitroaromatic compound degradation. Genetic cloning and expression of cnbH in Escherichia coli revealed that CnbH catalyzed the conversion of 2A5CM into 2H5CM and ammonium. Four other genes (cnbR, cnbE, cnbF, and cnbI) were tentatively identified according to their high sequence identities to other functionally identified genes. It was proposed that CnbH might represent a novel type of deaminase and be involved in a novel partial reductive pathway for chloronitrobenzene or nitrobenzene degradation.

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Gajula, Kiran S., Peter J. Huwe, Charlie Y. Mo, Daniel J. Crawford, James T. Stivers, Ravi Radhakrishnan et Rahul M. Kohli. « High-throughput mutagenesis reveals functional determinants for DNA targeting by activation-induced deaminase ». Nucleic Acids Research 42, n^o 15 (26 juillet 2014) : 9964–75. http://dx.doi.org/10.1093/nar/gku689.

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Abstract Antibody maturation is a critical immune process governed by the enzyme activation-induced deaminase (AID), a member of the AID/APOBEC DNA deaminase family. AID/APOBEC deaminases preferentially target cytosine within distinct preferred sequence motifs in DNA, with specificity largely conferred by a small 9–11 residue protein loop that differs among family members. Here, we aimed to determine the key functional characteristics of this protein loop in AID and to thereby inform our understanding of the mode of DNA engagement. To this end, we developed a methodology (Sat-Sel-Seq) that couples saturation mutagenesis at each position across the targeting loop, with iterative functional selection and next-generation sequencing. This high-throughput mutational analysis revealed dominant characteristics for residues within the loop and additionally yielded enzymatic variants that enhance deaminase activity. To rationalize these functional requirements, we performed molecular dynamics simulations that suggest that AID and its hyperactive variants can engage DNA in multiple specific modes. These findings align with AID's competing requirements for specificity and flexibility to efficiently drive antibody maturation. Beyond insights into the AID-DNA interface, our Sat-Sel-Seq approach also serves to further expand the repertoire of techniques for deep positional scanning and may find general utility for high-throughput analysis of protein function.

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Maas, Stefan, Thorsten Melcher et Peter H. Seeburg. « Mammalian RNA-dependent deaminases and edited mRNAs ». Current Opinion in Cell Biology 9, n^o 3 (juin 1997) : 343–49. http://dx.doi.org/10.1016/s0955-0674(97)80006-3.

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Chiu, Ya-Lin, et Warner C. Greene. « Multifaceted antiviral actions of APOBEC3 cytidine deaminases ». Trends in Immunology 27, n^o 6 (juin 2006) : 291–97. http://dx.doi.org/10.1016/j.it.2006.04.003.

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Köck, Josef, et Hubert E. Blum. « Hypermutation of hepatitis B virus genomes by APOBEC3G, APOBEC3C and APOBEC3H ». Journal of General Virology 89, n^o 5 (1 mai 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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Hossain, Gazi Sakir, Hyun-dong Shin, Jianghua Li, Miao Wang, Guocheng Du, Long Liu et Jian Chen. « Integrating error-prone PCR and DNA shuffling as an effective molecular evolution strategy for the production of α-ketoglutaric acid byl-amino acid deaminase ». RSC Advances 6, n^o 52 (2016) : 46149–58. http://dx.doi.org/10.1039/c6ra02940j.

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Gaded, Vandana, et Ruchi Anand. « Nucleobase deaminases : a potential enzyme system for new therapies ». RSC Advances 8, n^o 42 (2018) : 23567–77. http://dx.doi.org/10.1039/c8ra04112a.

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Bishop, Kate N., Rebecca K. Holmes et Michael H. Malim. « Antiviral Potency of APOBEC Proteins Does Not Correlate with Cytidine Deamination ». Journal of Virology 80, n^o 17 (1 septembre 2006) : 8450–58. http://dx.doi.org/10.1128/jvi.00839-06.

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ABSTRACT The human cytidine deaminases APOBEC3G (hA3G) and APOBEC3F (hA3F) are intracellular antiretroviral factors that can hypermutate nascent reverse transcripts and inhibit the replication of human immunodeficiency virus type 1 (HIV-1). Both enzymes have two cytidine deaminase motifs, although only the C-terminal motif is catalytic. Current models of APOBEC protein function imply editing is the principal mechanism of antiviral activity. In particular, hA3G is a more potent inhibitor of HIV-1 infectivity than hA3F and also induces a greater frequency of mutations in HIV-1 cDNA. We used hA3G/hA3F chimeric proteins to investigate whether cytidine deaminase potential reflects antiviral potency. We show here that the origin of the C-terminal deaminase motif is sufficient to determine the degree of mutation induced in a bacterial assay that measures mutations in chromosomal DNA. In contrast, this was not the case in the context of HIV-1 infection where the N-terminal deaminase motif also modulated the editing capabilities of the chimeras. Surprisingly, although three of the chimeric proteins induced levels of mutation that approximated those of parental hA3F, they displayed lower levels of antiviral activity. Most importantly, real-time PCR experiments revealed that the quantity of reverse transcripts detected in target cells, rather than the mutational burden carried by such DNAs, corresponded closely with viral infectivity. In other words, the antiviral phenotype of APOBEC proteins correlates with their ability to prevent the accumulation of reverse transcripts and not with the induction of hypermutation.

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Browne, Edward P., et Dan R. Littman. « Species-Specific Restriction of Apobec3-Mediated Hypermutation ». Journal of Virology 82, n^o 3 (21 novembre 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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Bzowska, Agnieszka, et David Shugar. « Properties of 5′-AMP Deaminase and its Inhibitors with the Aid of a Continuous Fluorimetric Assay with Formycin-5′-phosphate as Substrate ». Zeitschrift für Naturforschung C 44, n^o 7-8 (1 août 1989) : 581–89. http://dx.doi.org/10.1515/znc-1989-7-808.

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A new continuous fluorimetric assay for AMP deaminase activity is described. The m ethod makes use of a fluorescent analog of 5′-AMP, formycin-5′-phosphate (5′-FM P), which undergoes deam ination to formycin B-5′-phosphate, not fluorescent at neutral pH. The pH -dependence for deamination of 5′-FMP is similar to that for 5′-AMP, but shifted about 0.2 units to more acidic pH. Deamination of 5′-FM P may also be followed spectrophotometrically at 306 nm, permitting better assays of crude extracts. Some kinetic results obtained by means of the new method for AMP deaminase from chick and rabbit skeletal muscle are presented. In particular it was found that the natural product of deamination, 5′-IMP exhibited allosteric inhibition of the chick enzyme with K, values 1.6mM , 1.2mM and 1.0mM at pH 5.8, 6.5 and 7.3, respectively. Activation by diadenosine tetraphosphate, Ap4A , reported for mouse muscle AMP deaminase, has not been noted for the chick enzyme. Inhibition by the transition state analogs, coformycin and 2′-deoxycoformycin, was observed for both rabbit and chick deaminases with Ki values ~ 1 μM and ~ 1.6 μM respectively. Kinetic data for coformycin-5′-phosphate show it to be a tight-binding inhibitor with K, < 0.6 × 10-9 M as compared to 1 × 10-9 m for 2′-deoxycoformycin-5′-phosphate.

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Greenwell-Wild, Teresa, Nancy Vázquez, Wenwen Jin, Zoila Rangel, Peter J. Munson et Sharon M. Wahl. « Interleukin-27 inhibition of HIV-1 involves an intermediate induction of type I interferon ». Blood 114, n^o 9 (27 août 2009) : 1864–74. http://dx.doi.org/10.1182/blood-2009-03-211540.

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Infection of CD4+ chemokine coreceptor+ targets by HIV is aided and abetted by the proficiency of HIV in eliminating or neutralizing host cell–derived defensive molecules. Among these innate protective molecules, a family of intracellular apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases, is constitutively expressed but inactivated by HIV viral infectivity factor. The ability of interferon-α (IFN-α) to augment cytidine deaminases offered the possibility that the balance between virus and target cell might be altered in favor of the host. Further characterization of transcriptional profiles induced by IFN-α using microarrays, with the intention to identify and dissociate retroviral countermaneuvers from associated toxicities, revealed multiple molecules with suspected antiviral activity, including IL-27. To establish whether IFN-α toxicity might be sidestepped through the use of downstream IL-27 against HIV, we examined whether IL-27 directly regulated cytidine deaminases. Although IL-27 inducesAPOBECs, it does so in a delayed fashion. Dissecting the underlying regulatory events uncovered an initial IL-27–dependent induction of IFN-α and/or IFN-β, which in turn, induces APOBEC3, inhibited by IFN-α/β receptor blockade. In addition to macrophages, the IL-27–IFN-α connection is operative in CD4+ T cells, consistent with an IFN-α–dependent pathway underlying host cell defense to HIV.

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Dafou, Dimitra, Eirini Kanata, Spyros Pettas, Nikolaos Bekas, Athanasios Dimitriadis, Garyfalia Kempapidou, Roza Lagoudaki et al. « RNA Editing Alterations Define Disease Manifestations in the Progression of Experimental Autoimmune Encephalomyelitis (EAE) ». Cells 11, n^o 22 (12 novembre 2022) : 3582. http://dx.doi.org/10.3390/cells11223582.

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RNA editing is an epitranscriptomic modification, leading to targeted changes in RNA transcripts. It is mediated by the action of ADAR (adenosine deaminases acting on double-stranded (ds) RNA and APOBEC (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like) deaminases and appears to play a major role in the pathogenesis of many diseases. Here, we assessed its role in experimental autoimmune encephalomyelitis (EAE), a widely used non-clinical model of autoimmune inflammatory diseases of the central nervous system (CNS), which resembles many aspects of human multiple sclerosis (MS). We have analyzed in silico data from microglia isolated at different timepoints through disease progression to identify the global editing events and validated the selected targets in murine tissue samples. To further evaluate the functional role of RNA editing, we induced EAE in transgenic animals lacking expression of APOBEC-1. We found that RNA-editing events, mediated by the APOBEC and ADAR deaminases, are significantly reduced throughout the course of disease, possibly affecting the protein expression necessary for normal neurological function. Moreover, the severity of the EAE model was significantly higher in APOBEC-1 knock-out mice, compared to wild-type controls. Our results implicate regulatory epitranscriptomic mechanisms in EAE pathogenesis that could be extrapolated to MS and other neurodegenerative disorders (NDs) with common clinical and molecular features.

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LIU, Chengqian, Yulia Mukienko, Chengxiang Wu et Andrey Zavialov. « Human adenosine deaminases control the immune cell responses to activation signals by reducing extracellular adenosine concentration ». Journal of Immunology 196, n^o 1_Supplement (1 mai 2016) : 124.63. http://dx.doi.org/10.4049/jimmunol.196.supp.124.63.

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Abstract Adenosine rapidly accumulates in the sites of inflammation and tumor growth. It binds to adenosine receptors expressed on the cell surface of immune cells and induces either suppression or activation of inflammatory responses to pathogens. In humans the level of extracellular adenosine is regulated by two adenosine deaminases ADA1 and ADA2. Decrease in ADAs concentration due to genetic defects in the ADA genes leads to serious perturbation in the immune system function while increase in ADA activity associates with numerous immune diseases and cancers. The immune responses to extracellular adenosine have largely been studied using pharmacological approach where non-hydrolysable adenosine receptors agonists substitute adenosine to form the activated state of adenosine receptors. On contrary, adenosine receptors bound to adenosine receptor antagonists mimic inactivated state of adenosine receptors. Here, the effect of adenosine receptor agonists and antagonists on the monocytes function as well as and T helper cell proliferation and differentiation was compared with the effect of adenosine and adenosine deaminases. It was demonstrated that adenosine deaminases control the immune cells responses to activation signals by reducing the concentration of extracellular adenosine and that the cells sensitivity to adenosine greatly depends on the type of the cell activation. Therefore, our data suggests that ADAs could be considered as new drug candidates for the treatment of immune disorders and cancers.

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Vieira, Valdimara C., et 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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Thuy-Boun, Alexander S., Justin M. Thomas, Herra L. Grajo, Cody M. Palumbo, SeHee Park, Luan T. Nguyen, Andrew J. Fisher et Peter A. Beal. « Asymmetric dimerization of adenosine deaminase acting on RNA facilitates substrate recognition ». Nucleic Acids Research 48, n^o 14 (29 juin 2020) : 7958–72. http://dx.doi.org/10.1093/nar/gkaa532.

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Abstract Adenosine deaminases acting on RNA (ADARs) are enzymes that convert adenosine to inosine in duplex RNA, a modification that exhibits a multitude of effects on RNA structure and function. Recent studies have identified ADAR1 as a potential cancer therapeutic target. ADARs are also important in the development of directed RNA editing therapeutics. A comprehensive understanding of the molecular mechanism of the ADAR reaction will advance efforts to develop ADAR inhibitors and new tools for directed RNA editing. Here we report the X-ray crystal structure of a fragment of human ADAR2 comprising its deaminase domain and double stranded RNA binding domain 2 (dsRBD2) bound to an RNA duplex as an asymmetric homodimer. We identified a highly conserved ADAR dimerization interface and validated the importance of these sequence elements on dimer formation via gel mobility shift assays and size exclusion chromatography. We also show that mutation in the dimerization interface inhibits editing in an RNA substrate-dependent manner for both ADAR1 and ADAR2.

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Eid, Ayman, Sahar Alshareef et Magdy M. Mahfouz. « CRISPR base editors : genome editing without double-stranded breaks ». Biochemical Journal 475, n^o 11 (11 juin 2018) : 1955–64. http://dx.doi.org/10.1042/bcj20170793.

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The CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 adaptive immunity system has been harnessed for genome editing applications across eukaryotic species, but major drawbacks, such as the inefficiency of precise base editing and off-target activities, remain. A catalytically inactive Cas9 variant (dead Cas9, dCas9) has been fused to diverse functional domains for targeting genetic and epigenetic modifications, including base editing, to specific DNA sequences. As base editing does not require the generation of double-strand breaks, dCas9 and Cas9 nickase have been used to target deaminase domains to edit specific loci. Adenine and cytidine deaminases convert their respective nucleotides into other DNA bases, thereby offering many possibilities for DNA editing. Such base-editing enzymes hold great promise for applications in basic biology, trait development in crops, and treatment of genetic diseases. Here, we discuss recent advances in precise gene editing using different platforms as well as their potential applications in basic biology and biotechnology.

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Isquith, Jane Marie, Adam Mark, Jessica Pham, Mary Donohoe, Luisa Ladel et Catriona Jamieson. « Abstract 899 : Effects of innate immune deaminase deregulation on initiation and progression of myeloproliferative neoplasms ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 899. http://dx.doi.org/10.1158/1538-7445.am2022-899.

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Abstract Inflammatory cytokine responsive APOBEC3 cytidine deaminases have been studied extensively with regard to innate immunity and more recently during cancer evolution. However, the mechanisms by which the APOBEC3 enzymes promote cancer initiation and progression in the malignant microenvironment remains to be investigated, especially in hematopoietic malignancies. Through whole genome and whole transcriptome sequencing analyses of MPN patient samples FACS sorted into stem and progenitor populations, we have found a cell type and context specific nature of these enzymes, notably the upregulation of APOBEC3C (A3C) in the high-risk Myelofibrosis (MF) stem cell population as compared to normal aged counterparts. Through lentiviral overexpression of each APOBEC3 enzyme, we can now study the effects of changes in APOBEC3 transcript level in relation to the known changes in expression seen in many cancers, focusing on the upregulation of A3C. Using these techniques, we have identified novel RNA and DNA editing targets, as well as differential gene expression patterns of each APOBEC3 in normal CD34+ cord blood and aged normal bone marrow. Gene set enrichment analysis (GSEA) performed on this dataset has exposed numerous deregulated pathways brought on by exaggerated levels of APOBEC3, including changes in splicing pathways. In addition, novel identification of the relationship between A3C and ADAR1, another innate immune deaminase, has important implications in initiation and prognosis of MPNs. Both A3C and ADAR1 transcript levels are elevated in high risk MF stem cells, and co-immunoprecipitation studies reveal a direct binding of the enzymes. Furthermore, we are able to study the detailed effects of editing by both A3C and ADAR1 using editase-deficient mutant constructs, allowing for a mechanistic look into the role of these deaminases and their deregulation in vitro and in vivo using patient samples and humanized mouse models. This novel connection, as well as the role of A3C in initiation and progression of hematopoietic malignancies will continued to be studied using this system to elucidate effects on proliferation, differentiation, self-renewal, and changes to the cell cycle, in hopes of creating both a marker of early detection and potentially a druggable target. Citation Format: Jane Marie Isquith, Adam Mark, Jessica Pham, Mary Donohoe, Luisa Ladel, Catriona Jamieson. Effects of innate immune deaminase deregulation on initiation and progression of myeloproliferative neoplasms [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 899.

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Martín, Susana, José M. Cuevas, Ana Grande-Pérez et Santiago F. Elena. « A putative antiviral role of plant cytidine deaminases ». F1000Research 6 (3 mai 2017) : 622. http://dx.doi.org/10.12688/f1000research.11111.1.

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Background: A mechanism of innate antiviral immunity operating against viruses infecting mammalian cells has been described during the last decade. Host cytidine deaminases (e.g., APOBEC3 proteins) edit viral genomes, giving rise to hypermutated nonfunctional viruses; consequently, viral fitness is reduced through lethal mutagenesis. By contrast, sub-lethal hypermutagenesis may contribute to virus evolvability by increasing population diversity. To prevent genome editing, some viruses have evolved proteins that mediate APOBEC3 degradation. The model plant Arabidopsis thaliana genome encodes nine cytidine deaminases (AtCDAs), raising the question of whether deamination is an antiviral mechanism in plants as well. Methods: Here we tested the effects of expression of AtCDAs on the pararetrovirus Cauliflower mosaic virus (CaMV). Two different experiments were carried out. First, we transiently overexpressed each one of the nine A. thaliana AtCDA genes in Nicotiana bigelovii plants infected with CaMV, and characterized the resulting mutational spectra, comparing them with those generated under normal conditions. Secondly, we created A. thaliana transgenic plants expressing an artificial microRNA designed to knock-out the expression of up to six AtCDA genes. This and control plants were then infected with CaMV. Virus accumulation and mutational spectra where characterized in both types of plants. Results: We have shown that the A. thaliana AtCDA1 gene product exerts a mutagenic activity, significantly increasing the number of G to A mutations in vivo, with a concomitant reduction in the amount of CaMV genomes accumulated. Furthermore, the magnitude of this mutagenic effect on CaMV accumulation is positively correlated with the level of AtCDA1 mRNA expression in the plant. Conclusions: Our results suggest that deamination of viral genomes may also work as an antiviral mechanism in plants.

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Martín, Susana, José M. Cuevas, Ana Grande-Pérez et Santiago F. Elena. « A putative antiviral role of plant cytidine deaminases ». F1000Research 6 (15 juin 2017) : 622. http://dx.doi.org/10.12688/f1000research.11111.2.

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Background: A mechanism of innate antiviral immunity operating against viruses infecting mammalian cells has been described during the last decade. Host cytidine deaminases (e.g., APOBEC3 proteins) edit viral genomes, giving rise to hypermutated nonfunctional viruses; consequently, viral fitness is reduced through lethal mutagenesis. By contrast, sub-lethal hypermutagenesis may contribute to virus evolvability by increasing population diversity. To prevent genome editing, some viruses have evolved proteins that mediate APOBEC3 degradation. The model plant Arabidopsis thaliana genome encodes nine cytidine deaminases (AtCDAs), raising the question of whether deamination is an antiviral mechanism in plants as well. Methods: Here we tested the effects of expression of AtCDAs on the pararetrovirus Cauliflower mosaic virus (CaMV). Two different experiments were carried out. First, we transiently overexpressed each one of the nine A. thaliana AtCDA genes in Nicotiana bigelovii plants infected with CaMV, and characterized the resulting mutational spectra, comparing them with those generated under normal conditions. Secondly, we created A. thaliana transgenic plants expressing an artificial microRNA designed to knock-out the expression of up to six AtCDA genes. This and control plants were then infected with CaMV. Virus accumulation and mutational spectra where characterized in both types of plants. Results: We have shown that the A. thaliana AtCDA1 gene product exerts a mutagenic activity, significantly increasing the number of G to A mutations in vivo, with a concomitant reduction in the amount of CaMV genomes accumulated. Furthermore, the magnitude of this mutagenic effect on CaMV accumulation is positively correlated with the level of AtCDA1 mRNA expression in the plant. Conclusions: Our results suggest that deamination of viral genomes may also work as an antiviral mechanism in plants.

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Nabel, Christopher S., Emily K. Schutsky et Rahul M. Kohli. « Molecular targeting of mutagenic AID and APOBEC deaminases ». Cell Cycle 13, n^o 2 (15 novembre 2013) : 171–72. http://dx.doi.org/10.4161/cc.27036.

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