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1
Hanzelka, P., and F. Kobza. "Genome induced mutation in Callistephus chinensis Ness. – evaluation of plant fertility and seed characteristics." Horticultural Science 31, No. 1 (November 25, 2011): 22–26. http://dx.doi.org/10.17221/3787-hortsci.
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Thousand seed weight (TSW, g), achene size (mm) and fertility were evaluated in polyploid plants of C<sub>0</sub> (1999) and C<sub>1</sub> (2000) generations. The fertility of polyploid plants was usually very low (more than 10× compared to diploid plants). Only one plant (genotype A (tm) 1) was found as a tetraploid individual with anomalously high fertility, high TSW and large size of achenes. TSW in polyploid plants was 2.6–4.13 g, in diploid plants 2.0–2.3 g. The achene size was mostly about 3.7 mm (diploid plants) and 4.0–4.8 mm (polyploid plants). Achene (seed) size and thousand seed weight (TSW) can be classified among indirect identification methods (size of stomata, number of chloroplasts in guard cells, etc.) of polyploid plants.
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Chen, Aaron Yun, Yong Luo, Fang Cheng, Yuning Sun, and Jianming Qiu. "Bocavirus Infection Induces Mitochondrion-Mediated Apoptosis and Cell Cycle Arrest at G2/M Phase." Journal of Virology 84, no. 11 (March 24, 2010): 5615–26. http://dx.doi.org/10.1128/jvi.02094-09.
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ABSTRACT Bocavirus is a newly classified genus of the family Parvovirinae. Infection with Bocavirus minute virus of canines (MVC) produces a strong cytopathic effect in permissive Walter Reed/3873D (WRD) canine cells. We have systematically characterized the MVC infection-produced cytopathic effect in WRD cells, namely, the cell death and cell cycle arrest, and carefully examined how MVC infection induces the cytopathic effect. We found that MVC infection induces an apoptotic cell death characterized by Bax translocalization to the mitochondrial outer membrane, disruption of the mitochondrial outer membrane potential, and caspase activation. Moreover, we observed that the activation of caspases occurred only when the MVC genome was replicating, suggesting that replication of the MVC genome induces apoptosis. MVC infection also induced a gradual cell cycle arrest from the S phase in early infection to the G2/M phase at a later stage, which was confirmed by the upregulation of cyclin B1 and phosphorylation of cdc2. Cell cycle arrest at the G2/M phase was reproduced by transfection of a nonreplicative NS1 knockout mutant of the MVC infectious clone, as well as by inoculation of UV-irradiated MVC. In contrast with other parvoviruses, only expression of the MVC proteins by transfection did not induce apoptosis or cell cycle arrest. Taken together, our results demonstrate that MVC infection induces a mitochondrion-mediated apoptosis that is dependent on the replication of the viral genome, and the MVC genome per se is able to arrest the cell cycle at the G2/M phase. Our results may shed light on the molecular pathogenesis of Bocavirus infection in general.
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Brodsky, Michael H., Brian T. Weinert, Garson Tsang, Yikang S. Rong, Nadine M. McGinnis, Kent G. Golic, Donald C. Rio, and Gerald M. Rubin. "Drosophila melanogaster MNK/Chk2 and p53 Regulate Multiple DNA Repair and Apoptotic Pathways following DNA Damage." Molecular and Cellular Biology 24, no. 3 (February 1, 2004): 1219–31. http://dx.doi.org/10.1128/mcb.24.3.1219-1231.2004.
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ABSTRACT We have used genetic and microarray analysis to determine how ionizing radiation (IR) induces p53-dependent transcription and apoptosis in Drosophila melanogaster. IR induces MNK/Chk2-dependent phosphorylation of p53 without changing p53 protein levels, indicating that p53 activity can be regulated without an Mdm2-like activity. In a genome-wide analysis of IR-induced transcription in wild-type and mutant embryos, all IR-induced increases in transcript levels required both p53 and the Drosophila Chk2 homolog MNK. Proapoptotic targets of p53 include hid, reaper, sickle, and the tumor necrosis factor family member Eiger. Overexpression of Eiger is sufficient to induce apoptosis, but mutations in Eiger do not block IR-induced apoptosis. Animals heterozygous for deletions that span the reaper, sickle, and hid genes exhibited reduced IR-dependent apoptosis, indicating that this gene complex is haploinsufficient for induction of apoptosis. Among the genes in this region, hid plays a central, dosage-sensitive role in IR-induced apoptosis. p53 and MNK/Chk2 also regulate DNA repair genes, including two components of the nonhomologous end-joining repair pathway, Ku70 and Ku80. Our results indicate that MNK/Chk2-dependent modification of Drosophila p53 activates a global transcriptional response to DNA damage that induces error-prone DNA repair as well as intrinsic and extrinsic apoptosis pathways.
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Redondo, Elise, Renate Krause-Sakate, Shu-Jun Yang, Hervé Lot, Olivier Le Gall, and Thierry Candresse. "Lettuce mosaic virus Pathogenicity Determinants in Susceptible and Tolerant Lettuce Cultivars Map to Different Regions of the Viral Genome." Molecular Plant-Microbe Interactions® 14, no. 6 (June 2001): 804–10. http://dx.doi.org/10.1094/mpmi.2001.14.6.804.
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Full-length infectious cDNA clones were constructed for two isolates (LMV-0 and LMV-E) of Lettuce mosaic virus (LMV), a member of the genus Potyvirus. These two isolates differ in pathogenicity in susceptible and tolerant-resistant lettuce cultivars. In susceptible plants, LMV-0 induces mild mosaic symptoms, whereas LMV-E induces severe stunting, leaf deformation, and a necrotic mosaic. In plants carrying either of the two probably allelic recessive resistance genes mo11 or mo12, LMV-0 is restricted partially to the inoculated leaves. When a systemic invasion does occur, however, symptoms fail to develop. LMV-E overcomes the protection afforded by the resistance genes, resulting in systemic mosaic symptoms. Analysis of the behavior of recombinants constructed between the two virus isolates determined that the HC-Pro protein of LMV-E causes the severe stunting and necrotic mosaic induced by this isolate in susceptible cultivars. In contrast, the ability to overcome mo1 resistance and induce symptoms in the resistant-tolerant cultivars was mapped to the 3′ half of the LMV-E genome. These results indicate that the ability to induce severe symptoms and to overcome the protection afforded by the recessive genes mo11 or mo12 are independent phenomena.
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Parish, Joanna L., Anna Kowalczyk, Hsin-Tien Chen, Geraldine E. Roeder, Richard Sessions, Malcolm Buckle, and Kevin Gaston. "E2 Proteins from High- and Low-Risk Human Papillomavirus Types Differ in Their Ability To Bind p53 and Induce Apoptotic Cell Death." Journal of Virology 80, no. 9 (May 1, 2006): 4580–90. http://dx.doi.org/10.1128/jvi.80.9.4580-4590.2006.
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ABSTRACT The E2 proteins from oncogenic (high-risk) human papillomaviruses (HPVs) can induce apoptotic cell death in both HPV-transformed and non-HPV-transformed cells. Here we show that the E2 proteins from HPV type 6 (HPV6) and HPV11, two nononcogenic (low-risk) HPV types, fail to induce apoptosis. Unlike the high-risk HPV16 E2 protein, these low-risk E2 proteins fail to bind p53 and fail to induce p53-dependent transcription activation. Interestingly, neither the ability of p53 to activate transcription nor the ability of p53 to bind DNA, are required for HPV16 E2-induced apoptosis in non-HPV-transformed cells. However, mutations that reduce the binding of the HPV16 E2 protein to p53 inhibit E2-induced apoptosis in non-HPV-transformed cells. In contrast, the interaction between HPV16 E2 and p53 is not required for this E2 protein to induce apoptosis in HPV-transformed cells. Thus, our data suggest that this high-risk HPV E2 protein induces apoptosis via two pathways. One pathway involves the binding of E2 to p53 and can operate in both HPV-transformed and non-HPV-transformed cells. The second pathway requires the binding of E2 to the viral genome and can only operate in HPV-transformed cells.
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Efimova, Olga A., Alla S. Koltsova, Mikhail I. Krapivin, Andrei V. Tikhonov, and Anna A. Pendina. "Environmental Epigenetics and Genome Flexibility: Focus on 5-Hydroxymethylcytosine." International Journal of Molecular Sciences 21, no. 9 (May 2, 2020): 3223. http://dx.doi.org/10.3390/ijms21093223.
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Convincing evidence accumulated over the last decades demonstrates the crucial role of epigenetic modifications for mammalian genome regulation and its flexibility. DNA methylation and demethylation is a key mechanism of genome programming and reprogramming. During ontogenesis, the DNA methylome undergoes both programmed changes and those induced by environmental and endogenous factors. The former enable accurate activation of developmental programs; the latter drive epigenetic responses to factors that directly or indirectly affect epigenetic biochemistry leading to alterations in genome regulation and mediating organism response to environmental transformations. Adverse environmental exposure can induce aberrant DNA methylation changes conducive to genetic dysfunction and, eventually, various pathologies. In recent years, evidence was derived that apart from 5-methylcytosine, the DNA methylation/demethylation cycle includes three other oxidative derivatives of cytosine—5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine. 5hmC is a predominantly stable form and serves as both an intermediate product of active DNA demethylation and an essential hallmark of epigenetic gene regulation. This makes 5hmC a potential contributor to epigenetically mediated responses to environmental factors. In this state-of-the-art review, we consolidate the latest findings on environmentally induced adverse effects on 5hmC patterns in mammalian genomes. Types of environmental exposure under consideration include hypnotic drugs and medicines (i.e., phenobarbital, diethylstilbestrol, cocaine, methamphetamine, ethanol, dimethyl sulfoxide), as well as anthropogenic pollutants (i.e., heavy metals, particulate air pollution, bisphenol A, hydroquinone, and pentachlorophenol metabolites). We put a special focus on the discussion of molecular mechanisms underlying environmentally induced alterations in DNA hydroxymethylation patterns and their impact on genetic dysfunction. We conclude that DNA hydroxymethylation is a sensitive biosensor for many harmful environmental factors each of which specifically targets 5hmC in different organs, cell types, and DNA sequences and induces its changes through a specific metabolic pathway. The associated transcriptional changes suggest that environmentally induced 5hmC alterations play a role in epigenetically mediated genome flexibility. We believe that knowledge accumulated in this review together with further studies will provide a solid basis for new approaches to epigenetic therapy and chemoprevention of environmentally induced epigenetic toxicity involving 5hmC patterns.
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Sanchez, David Jesse, Daniel Miranda, Vaithilingaraja Arumugaswami, Seungmin Hwang, Adam E. Singer, Ashkon Senaati, Arash Shahangian, Moon Jung Song, Ren Sun, and Genhong Cheng. "A Repetitive Region of Gammaherpesvirus Genomic DNA Is a Ligand for Induction of Type I Interferon." Journal of Virology 82, no. 5 (December 12, 2007): 2208–17. http://dx.doi.org/10.1128/jvi.01718-07.
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ABSTRACT Innate immune responses against viral infection, especially the induction of type I interferon, are critical for limiting the replication of the virus. Although it has been shown that DNA can induce type I interferon, to date no natural DNA ligand of a virus that induces type I interferon has been described. Here we screened the genome of murine gammaherpesvirus 68 with mutations at various genomic locations to map the region of DNA that induces type I interferon. A repetitive region termed the 100-base-pair repeat region is a ligand that is both necessary and sufficient for the viral genomic DNA to induce type I interferon. A region colinear with this ligand in the genome of Kaposi's sarcoma-associated herpesvirus also induces type I interferon. We have thus defined a repetitive region of the genomes of gammaherpesviruses as the first natural DNA virus ligand that induces type I interferon.
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Holthusen, Kirsten, Pooja Talaty, and David N. Everly. "Regulation of Latent Membrane Protein 1 Signaling through Interaction with Cytoskeletal Proteins." Journal of Virology 89, no. 14 (May 6, 2015): 7277–90. http://dx.doi.org/10.1128/jvi.00321-15.
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ABSTRACTLatent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) induces constitutive signaling in EBV-infected cells to ensure the survival of the latently infected cells. LMP1 is localized to lipid raft domains to induce signaling. In the present study, a genome-wide screen based on bimolecular fluorescence complementation (BiFC) was performed to identify LMP1-binding proteins. Several actin cytoskeleton-associated proteins were identified in the screen. Overexpression of these proteins affected LMP1-induced signaling. BiFC between the identified proteins and LMP1 was localized to lipid raft domains and was dependent on LMP1-induced signaling. Proximity biotinylation assays with LMP1 induced biotinylation of the actin-associated proteins, which were shifted in molecular mass. Together, the findings of this study suggest that the association of LMP1 with lipid rafts is mediated at least in part through interactions with the actin cytoskeleton.IMPORTANCELMP1 signaling requires oligomerization, lipid raft partitioning, and binding to cellular adaptors. The current study utilized a genome-wide screen to identify several actin-associated proteins as candidate LMP1-binding proteins. The interaction between LMP1 and these proteins was localized to lipid rafts and dependent on LMP1 signaling. This suggests that the association of LMP1 with lipid rafts is mediated through interactions with actin-associated proteins.
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Wei, Taiyun, Tyng-Shyan Huang, Jamie McNeil, Jean-François Laliberté, Jian Hong, Richard S. Nelson, and Aiming Wang. "Sequential Recruitment of the Endoplasmic Reticulum and Chloroplasts for Plant Potyvirus Replication." Journal of Virology 84, no. 2 (November 11, 2009): 799–809. http://dx.doi.org/10.1128/jvi.01824-09.
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ABSTRACT The replication of positive-strand RNA viruses occurs in cytoplasmic membrane-bound virus replication complexes (VRCs). Depending on the virus, distinct cellular organelles such as the endoplasmic reticulum (ER), chloroplast, mitochondrion, endosome, and peroxisome are recruited for the formation of VRC-associated membranous structures. Previously, the 6,000-molecular-weight protein (6K) of plant potyviruses was shown to be an integral membrane protein that induces the formation of 6K-containing membranous vesicles at endoplasmic reticulum (ER) exit sites for potyvirus genome replication. Here, we present evidence that the 6K-induced vesicles predominantly target chloroplasts, where they amalgamate and induce chloroplast membrane invaginations. The vesicular transport pathway and actomyosin motility system are involved in the trafficking of the 6K vesicles from the ER to chloroplasts. Viral RNA, double-stranded RNA, and viral replicase components are concentrated at the 6K vesicles that associate with chloroplasts in infected cells, suggesting that these chloroplast-bound 6K vesicles are the site for potyvirus replication. Taken together, these results suggest that plant potyviruses sequentially recruit the ER and chloroplasts for their genome replication.
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Durant, Stephen T., Kimberly S. Paffett, Meena Shrivastav, Graham S. Timmins, William F. Morgan, and Jac A. Nickoloff. "UV Radiation Induces Delayed Hyperrecombination Associated with Hypermutation in Human Cells." Molecular and Cellular Biology 26, no. 16 (August 15, 2006): 6047–55. http://dx.doi.org/10.1128/mcb.00444-06.
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ABSTRACT Ionizing radiation induces delayed genomic instability in human cells, including chromosomal abnormalities and hyperrecombination. Here, we investigate delayed genome instability of cells exposed to UV radiation. We examined homologous recombination-mediated reactivation of a green fluorescent protein (GFP) gene in p53-proficient human cells. We observed an ∼5-fold enhancement of delayed hyperrecombination (DHR) among cells surviving a low dose of UV-C (5 J/m2), revealed as mixed GFP+/− colonies. UV-B did not induce DHR at an equitoxic (75 J/m2) dose or a higher dose (150 J/m2). UV is known to induce delayed hypermutation associated with increased oxidative stress. We found that hypoxanthine phosphoribosyltransferase (HPRT) mutation frequencies were ∼5-fold higher in strains derived from GFP+/− (DHR) colonies than in strains in which recombination was directly induced by UV (GFP+ colonies). To determine whether hypermutation was directly caused by hyperrecombination, we analyzed hprt mutation spectra. Large-scale alterations reflecting large deletions and insertions were observed in 25% of GFP+ strains, and most mutants had a single change in HPRT. In striking contrast, all mutations arising in the hypermutable GFP+/− strains were small (1- to 2-base) changes, including substitutions, deletions, and insertions (reminiscent of mutagenesis from oxidative damage), and the majority were compound, with an average of four hprt mutations per mutant. The absence of large hprt deletions in DHR strains indicates that DHR does not cause hypermutation. We propose that UV-induced DHR and hypermutation result from a common source, namely, increased oxidative stress. These two forms of delayed genome instability may collaborate in skin cancer initiation and progression.
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Alvarez, Francisco J., and James B. Konopka. "Identification of anN-Acetylglucosamine Transporter That Mediates Hyphal Induction inCandida albicans." Molecular Biology of the Cell 18, no. 3 (March 2007): 965–75. http://dx.doi.org/10.1091/mbc.e06-10-0931.
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The sugar N-acetylglucosamine (GlcNAc) plays an important role in nutrient sensing and cellular regulation in a wide range of organisms from bacteria to humans. In the fungal pathogen Candida albicans, GlcNAc induces a morphological transition from budding to hyphal growth. Proteomic comparison of plasma membrane proteins from buds and from hyphae induced by GlcNAc identified a novel hyphal protein (Ngt1) with similarity to the major facilitator superfamily of transporters. An Ngt1-GFP fusion was detected in the plasma membrane after induction with GlcNAc, but not other related sugars. Ngt1-GFP was also induced by macrophage phagocytosis, suggesting a role for the GlcNAc response in signaling entry into phagolysosomes. NGT1 is needed for efficient GlcNAc uptake and for the ability to induce hyphae at low GlcNAc concentrations. High concentrations of GlcNAc could bypass the need for NGT1 to induce hyphae, indicating that elevated intracellular levels of GlcNAc induce hyphal formation. Expression of NGT1 in Saccharomyces cerevisiae promoted GlcNAc uptake, indicating that Ngt1 acts directly as a GlcNAc transporter. Transport mediated by Ngt1 was specific, as other sugars could not compete for the uptake of GlcNAc. Thus, Ngt1 represents the first eukaryotic GlcNAc transporter to be discovered. The presence of NGT1 homologues in the genome sequences of a wide range of eukaryotes from yeast to mammals suggests that they may also function in the cellular processes regulated by GlcNAc, including those that underlie important diseases such as cancer and diabetes.
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Hammond, Ester M., Daniel J. Mandell, Ali Salim, Adam J. Krieg, Thomas M. Johnson, Haider A. Shirazi, Laura D. Attardi, and Amato J. Giaccia. "Genome-Wide Analysis of p53 under Hypoxic Conditions." Molecular and Cellular Biology 26, no. 9 (May 1, 2006): 3492–504. http://dx.doi.org/10.1128/mcb.26.9.3492-3504.2006.
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ABSTRACT Hypoxia is an important nongenotoxic stress that modulates the tumor suppressor activity of p53 during malignant progression. In this study, we investigated how genotoxic and nongenotoxic stresses regulate p53 association with chromatin, p53 transcriptional activity, and p53-dependent apoptosis. We found that genotoxic and nongenotoxic stresses result in the accumulation and binding of the p53 tumor suppressor protein to the same cognate binding sites in chromatin. However, it is the stress that determines whether downstream signaling is mediated by association with transcriptional coactivators. In contrast to p53 induced by DNA-damaging agents, hypoxia-induced p53 has primarily transrepression activity. Using extensive microarray analysis, we identified families of repressed targets of p53 that are involved in cell signaling, DNA repair, cell cycle control, and differentiation. Following our previous study on the contribution of residues 25 and 26 to p53-dependent hypoxia-induced apoptosis, we found that residues 25-26 and 53-54 and the polyproline- and DNA-binding regions are also required for both gene repression and the induction of apoptosis by p53 during hypoxia. This study defines a new role for residues 53 and 54 of p53 in regulating transrepression and demonstrates that 25-26 and 53-54 work in the same pathway to induce apoptosis through gene repression.
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Nováček, Jiří, Marta Šiborová, Martin Benešík, Roman Pantůček, Jiří Doškař, and Pavel Plevka. "Structure and genome release of Twort-like Myoviridae phage with a double-layered baseplate." Proceedings of the National Academy of Sciences 113, no. 33 (July 28, 2016): 9351–56. http://dx.doi.org/10.1073/pnas.1605883113.
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Bacteriophages from the family Myoviridae use double-layered contractile tails to infect bacteria. Contraction of the tail sheath enables the tail tube to penetrate through the bacterial cell wall and serve as a channel for the transport of the phage genome into the cytoplasm. However, the mechanisms controlling the tail contraction and genome release of phages with “double-layered” baseplates were unknown. We used cryo-electron microscopy to show that the binding of the Twort-like phage phi812 to the Staphylococcus aureus cell wall requires a 210° rotation of the heterohexameric receptor-binding and tripod protein complexes within its baseplate about an axis perpendicular to the sixfold axis of the tail. This rotation reorients the receptor-binding proteins to point away from the phage head, and also results in disruption of the interaction of the tripod proteins with the tail sheath, hence triggering its contraction. However, the tail sheath contraction of Myoviridae phages is not sufficient to induce genome ejection. We show that the end of the phi812 double-stranded DNA genome is bound to one protein subunit from a connector complex that also forms an interface between the phage head and tail. The tail sheath contraction induces conformational changes of the neck and connector that result in disruption of the DNA binding. The genome penetrates into the neck, but is stopped at a bottleneck before the tail tube. A subsequent structural change of the tail tube induced by its interaction with the S. aureus cell is required for the genome’s release.
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Ng, K. H., J. Maigne, and J. Deschatrette. "The inductive effect of a human DNA sequence (HALF1) on the differentiation of a variant rat hepatoma cell (C2) is restricted to episomal forms of the molecule." Journal of Cell Science 108, no. 4 (April 1, 1995): 1703–13. http://dx.doi.org/10.1242/jcs.108.4.1703.
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HALF1, a 4.3 kb human DNA sequence, was originally identified as a double-stranded, closed-circular DNA molecule in revertants from a dedifferentiated rat hepatoma cell (C2) transfected with human liver DNA. Here we report its specific properties in inducing the transition to the hepatic phenotype. (i) In vitro recircularized HALF1 induces reversion after a minimum time lag of 7 days post-transfection. (ii) After induction, the presence of HALF1 is not required for maintaining the induced hepatic state. (iii) HALF1 is detected as a sequence integrated in high molecular mass DNA of human liver. (iv) HALF1 monomer or dimer plasmid constructs do not induce reversion when integrated into the genome of transfectants. (v) Short ubiquitous RNA transcripts (approximately 400 bases) are detected with specific HALF1 probes. These results indicate that the reversion process is linked to the presence of HALF1 extrachromosomal molecules.
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Hein, Jennifer, Sergei Boichuk, Jiaping Wu, Yuan Cheng, Raimundo Freire, Parmjit S. Jat, Thomas M. Roberts, and Ole V. Gjoerup. "Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding." Journal of Virology 83, no. 1 (October 15, 2008): 117–27. http://dx.doi.org/10.1128/jvi.01515-08.
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ABSTRACT Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that is important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shown to lead to the induction of DNA damage response signaling, which is required for efficient viral replication. However, it was not clear if LT is sufficient to induce the damage response and, if so, what the genetic requirements and functional consequences might be. Here, we show that the expression of LT alone, without a replication origin, can induce key DNA damage response markers including the accumulation of γ-H2AX and 53BP1 in nuclear foci. Other DNA damage-signaling components downstream of ATM/ATR kinases were induced, including chk1 and chk2. LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins. Stimulation of the damage response by LT depends mainly on binding to Bub1 rather than to the retinoblastoma protein. LT has long been known to stabilize p53 despite functionally inactivating it. We show that the activation of a DNA damage response by LT via Bub1 appears to play a major role in p53 stabilization by promoting the phosphorylation of p53 at Ser15. Accompanying the DNA damage response, LT induces tetraploidy, which is also dependent on Bub1 binding. Taken together, our data suggest that LT, via Bub1 binding, breaches genome integrity mechanisms, leading to DNA damage responses, p53 stabilization, and tetraploidy.
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Murray, Vincent, Megan E. Hardie, and Shweta D. Gautam. "Comparison of Different Methods to Determine the DNA Sequence Preference of Ionising Radiation-Induced DNA Damage." Genes 11, no. 1 (December 20, 2019): 8. http://dx.doi.org/10.3390/genes11010008.
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Ionising radiation (IR) is known to induce a wide variety of lesions in DNA. In this review, we compared three different techniques that examined the DNA sequence preference of IR-induced DNA damage at nucleotide resolution. These three techniques were: the linear amplification/polymerase stop assay, the end-labelling procedure, and Illumina next-generation genome-wide sequencing. The DNA sequence preference of IR-induced DNA damage was compared in purified DNA sequences including human genomic DNA. It was found that the DNA sequence preference of IR-induced DNA damage identified by the end-labelling procedure (that mainly detected single-strand breaks) and Illumina next-generation genome-wide sequencing (that mainly detected double-strand breaks) was at C nucleotides, while the linear amplification/polymerase stop assay (that mainly detected base damage) was at G nucleotides. A consensus sequence at the IR-induced DNA damage was found to be 5′-AGGC*C for the end-labelling technique, 5′-GGC*MH (where * is the cleavage site, M is A or C, H is any nucleotide except G) for the genome-wide technique, and 5′-GG* for the linear amplification/polymerase stop procedure. These three different approaches are important because they provide a deeper insight into the mechanism of action of IR-induced DNA damage.
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Cleveland, Susan M., and Utpal P. Dave. "Insertional Activation of GLI2 in Adult T-Cell Leukemia/Lymphoma." Blood 110, no. 11 (November 16, 2007): 4149. http://dx.doi.org/10.1182/blood.v110.11.4149.4149.
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Abstract Retroviruses induce cancer by integrating into the cellular genome and activating oncogenes or inactivating tumor suppressor genes. Human T-cell Leukemia Virus type 1 (HTLV-1), a complex retrovirus, induces Adult T-cell Leukemia/Lymphoma (ATLL) after a latency of over 30 years and in only 5% of carriers. The long latency and incomplete penetrance is similar to how slow transforming retroviruses induce cancer in mice and imply multiple oncogenic “hits” need to accumulate for clinically apparent disease. Insertional mutagenesis may be one mechanism by which ATLL develops. We used splinkerette-PCR to clone and map insertion sites from an HTLV-1 infected T-cell line, Hut-102. We identified an HTLV-1 insertion 5′ of the GLI2 gene, formerly known as Tax-Helper-Protein-1. We found GLI2 was up-regulated by promoter insertion. Interestingly, we found GLI2 protein occupied the HTLV-1 Long Terminal Repeat. The effect of GLI2 expression on viral expression was investigated by knockdown of GLI2 in Hut-102 cells. Our results show that retroviral insertional mutagenesis can be an important mechanism in HTLV-1-induced leukemias and lymphomas.
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Allen, Jawara, Shaoguang Wu, Xinqun Wu, and Cynthia Sears. "2611. Enterotoxigenic Bacteroides fragilis Alters the Genome of Colon Epithelial Cells." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S908. http://dx.doi.org/10.1093/ofid/ofz360.2289.
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Abstract Background Individuals born in 1990 have twice the risk of developing colon cancer and four times the risk of developing rectal cancer as those born in 1950. The gut microbiome is being proposed as a potential contributor to this difference because of the surge in obesity in the United States, the link between obesity and gut dysbiosis, and the growing number of studies which have associated a dysbiotic gut microbiome with CRC. Enterotoxigenic Bacteroides fragilis (ETBF) is one of the bacteria most studied in relation to CRC development; it is found at a higher frequency in both the stool and mucosa of CRC patients, and it rapidly induces tumor formation in an Apcmin/+ mouse model of CRC. In this model, tumor formation typically occurs via loss of heterozygosity (LOH) of the Apc gene, the genetic mutation found in approximately 80% of sporadic CRC cases. ETBF produces a potent exotoxin (BFT) which induces E-cadherin cleavage, β-catenin nuclear localization and colonic epithelial cell proliferation. But we still do not understand how these downstream effects cause lasting changes in the genome of colon epithelial cells that then initiate tumor formation and growth. As cancer is ultimately a disease that arises and progresses via changes in the genome, understanding these interactions is essential. Methods We hypothesize that ETBF induces DNA mutations via BFT that encourage tumor formation, and enhance tumor growth. To test this hypothesis, we performed whole-exome sequencing on tumors and normal tissue isolated from Apcmin/+ mice after ETBF or sham inoculation. Additionally, we isolated colon organoids from Apcmin/+ mouse normal tissue (colonoids) and Apcmin/+ mouse tumors (tumoroids) after ETBF or sham inoculation. We performed in vitro DNA damage assays and qPCR for Apc LOH on these colon organoids. Results Our preliminary data indicate that ETBF-induced tumors have lower rates of Apc LOH and that double-stranded DNA breaks are observed as soon as 3-hours after BFT treatment of colonoids and as soon as 72-hours after ETBF inoculation. Conclusion These data suggest that in vivo, ETBF may induce mutations in cancer-driver genes which cause tumor formation via pathways other than somatic recombination at the Apc locus, a result we are now testing with additional (N = 19) whole-exome tumor sequencing in-progress. Disclosures All authors: No reported disclosures.
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Kerlan, Camille, Olga V. Nikolaeva, Xiaojun Hu, Teresa Meacham, Stewart M. Gray, and Alexander V. Karasev. "Identification of the Molecular Make-Up of the Potato virus Y Strain PVYZ: Genetic Typing of PVYZ-NTN." Phytopathology® 101, no. 9 (September 2011): 1052–60. http://dx.doi.org/10.1094/phyto-11-10-0317.
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Potato virus Y (PVY) strains were originally defined by interactions with different resistance genes in standard potato cultivars. Five distinct strain groups are defined that cause local or systemic hypersensitive responses (HRs) in genetic background with a corresponding N gene: PVYO, PVYN, PVYC, PVYZ, and PVYE. The nucleotide sequences of multiple isolates of PVYO and PVYN differ from each other by ≈8% along their genomes. Additionally, complete genome sequences of multiple recombinant isolates are composed of segments of parental PVYO and PVYN sequences. Here, we report that recombinant isolate PVY-L26 induces an HR in potato ‘Maris Bard’ carrying the putative Nz gene, and is not recognized by two other resistance genes, Nc and Nytbr. These genetic responses in potato, combined with the inability of PVY-L26 to induce vein necrosis in tobacco, clearly define it as an isolate from the PVYZ strain group and provide the first information on genome structure and sequence of PVYZ. The genome of PVY-L26 displays typical features of European NTN-type isolates with three recombinant junctions (PVYEU-NTN), and the PVY-L26 is named PVYZ-NTN. Three typical PVYNTN isolates and two PVYN isolates, all inducing vein necrosis in tobacco, were compared with PVY-L26. One PVYNTN isolate elicited HR reactions in Maris Bard, similar to PVY-L26, while two induced a severe systemic HR-like reaction quite different from the quasi-symptomless reaction induced by two PVYN isolates. ‘Yukon Gold’ potato from North America produced HR against several PVYNTN isolates, including PVY-L26, but only late and limited systemic necrosis against one PVYN isolate. Consequently, according to symptoms in potato indicators, both PVYZ and PVYNTN isolates appeared biologically very close and clearly distinct from PVYO and PVYN strain groups.
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Oyarzún-Arrau, Aarón, Luis Alonso-Palomares, Fernando Valiente-Echeverría, Fabiola Osorio, and Ricardo Soto-Rifo. "Crosstalk between RNA Metabolism and Cellular Stress Responses during Zika Virus Replication." Pathogens 9, no. 3 (February 25, 2020): 158. http://dx.doi.org/10.3390/pathogens9030158.
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Zika virus (ZIKV) is a mosquito-borne virus associated with neurological disorders such as Guillain-Barré syndrome and microcephaly. In humans, ZIKV is able to replicate in cell types from different tissues including placental cells, neurons, and microglia. This intricate virus-cell interaction is accompanied by virally induced changes in the infected cell aimed to promote viral replication as well as cellular responses aimed to counteract or tolerate the virus. Early in the infection, the 11-kb positive-sense RNA genome recruit ribosomes in the cytoplasm and the complex is translocated to the endoplasmic reticulum (ER) for viral protein synthesis. In this process, ZIKV replication is known to induce cellular stress, which triggers both the expression of innate immune genes and the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α), shutting-off host protein synthesis. Remodeling of the ER during ZIKV replication also triggers the unfolded protein response (UPR), which induces changes in the cellular transcriptional landscapes aimed to tolerate infection or trigger apoptosis. Alternatively, ZIKV replication induces changes in the adenosine methylation patterns of specific host mRNAs, which have different consequences in viral replication and cellular fate. In addition, the ZIKV RNA genome undergoes adenosine methylation by the host machinery, which results in the inhibition of viral replication. However, despite these relevant findings, the full scope of these processes to the outcome of infection remains poorly elucidated. This review summarizes relevant aspects of the complex crosstalk between RNA metabolism and cellular stress responses against ZIKV and discusses their possible impact on viral pathogenesis.
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Suehiro, Noriko, Tomohide Natsuaki, Tomoko Watanabe, and Seiichi Okuda. "An important determinant of the ability of Turnip mosaic virus to infect Brassica spp. and/or Raphanus sativus is in its P3 protein." Journal of General Virology 85, no. 7 (July 1, 2004): 2087–98. http://dx.doi.org/10.1099/vir.0.79825-0.
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Turnip mosaic virus (TuMV, genus Potyvirus, family Potyviridae) infects mainly cruciferous plants. Isolates Tu-3 and Tu-2R1 of TuMV exhibit different infection phenotypes in cabbage (Brassica oleracea L.) and Japanese radish (Raphanus sativus L.). Infectious full-length cDNA clones, pTuC and pTuR1, were constructed from isolates Tu-3 and Tu-2R1, respectively. Progeny virus derived from infections with pTuC induced systemic chlorotic and ringspot symptoms in infected cabbage, but no systemic infection in radish. Virus derived from plants infected with pTuR1 induced a mild chlorotic mottle in cabbage and infected radish systemically to induce mosaic symptoms. By exchanging genome fragments between the two virus isolates, the P3-coding region was shown to be responsible for systemic infection by TuMV and the symptoms it induces in cabbage and radish. Moreover, exchanges of smaller parts of the P3 region resulted in recombinants that induced complex infection phenotypes, especially the combination of pTuC-derived N-terminal sequence and pTuR1-derived C-terminal sequence. Analysis by tissue immunoblotting of the inoculated leaves showed that the distributions of P3-chimeric viruses differed from those of the parents, and that the origin of the P3 components affected not only virus accumulation, but also long-distance movement. These results suggest that the P3 protein is an important factor in the infection cycle of TuMV and in determining the host range of this and perhaps other potyviruses.
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Wang, Longfei, Shuai Cao, Peitong Wang, Kening Lu, Qingxin Song, Fang-Jie Zhao, and Z. Jeffrey Chen. "DNA hypomethylation in tetraploid rice potentiates stress-responsive gene expression for salt tolerance." Proceedings of the National Academy of Sciences 118, no. 13 (March 26, 2021): e2023981118. http://dx.doi.org/10.1073/pnas.2023981118.
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Polyploidy is a prominent feature for genome evolution in many animals and all flowering plants. Plant polyploids often show enhanced fitness in diverse and extreme environments, but the molecular basis for this remains elusive. Soil salinity presents challenges for many plants including agricultural crops. Here we report that salt tolerance is enhanced in tetraploid rice through lower sodium uptake and correlates with epigenetic regulation of jasmonic acid (JA)–related genes. Polyploidy induces DNA hypomethylation and potentiates genomic loci coexistent with many stress-responsive genes, which are generally associated with proximal transposable elements (TEs). Under salt stress, the stress-responsive genes including those in the JA pathway are more rapidly induced and expressed at higher levels in tetraploid than in diploid rice, which is concurrent with increased jasmonoyl isoleucine (JA-Ile) content and JA signaling to confer stress tolerance. After stress, elevated expression of stress-responsive genes in tetraploid rice can induce hypermethylation and suppression of the TEs adjacent to stress-responsive genes. These induced responses are reproducible in a recurring round of salt stress and shared between two japonica tetraploid rice lines. The data collectively suggest a feedback relationship between polyploidy-induced hypomethylation in rapid and strong stress response and stress-induced hypermethylation to repress proximal TEs and/or TE-associated stress-responsive genes. This feedback regulation may provide a molecular basis for selection to enhance adaptation of polyploid plants and crops during evolution and domestication.
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Inman, Gareth J., Ulrich K. Binné, Gillian A. Parker, Paul J. Farrell, and Martin J. Allday. "Activators of the Epstein-Barr Virus Lytic Program Concomitantly Induce Apoptosis, but Lytic Gene Expression Protects from Cell Death." Journal of Virology 75, no. 5 (March 1, 2001): 2400–2410. http://dx.doi.org/10.1128/jvi.75.5.2400-2410.2001.
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ABSTRACT Expression of the lytic cycle genes of Epstain-Barr virus (EBV) is induced in type I Burkitt's lymphoma-derived cells by treatment with phorbol esters (e.g., phorbol myristate acetate [PMA]), anti-immunoglobulin, or the cytokine transforming growth factor β (TGF-β). Concomitantly, all these agents induce apoptosis as judged by a sub-G1 fluorescence-activated cell sorter (FACS) profile, proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. However, caspase activation is not required for induction of the lytic cycle since the latter is not blocked by the caspase inhibitor ZVAD. Furthermore, not all agents that induce apoptosis in these cultures (for example, cisplatin and ceramide) induce the EBV lytic programme. Although it is closely associated with the lytic cycle, apoptosis is neither necessary nor sufficient for its activation. Multiparameter FACS analysis of cultures treated with PMA, anti-Ig, or TGF-β revealed BZLF1-expressing cells distributed in different phases of the cell cycle according to which inducer was used. However, BZLF1-positive cells did not appear to undergo apoptosis and accumulate with a sub-G1 DNA content, irrespective of the inducer used. This result, which suggests that lytic gene expression is protective, was confirmed and extended by immunofluorescence staining doubled with TUNEL analysis. BZLF1- and also gp350-expressing cells were almost always shown to be negative for TUNEL staining. Similar experiments using EBV-positive and -negative subclones of Akata BL cells carrying an episomal BZLF1 reporter plasmid confirmed that protection from apoptosis was associated with the presence of the EBV genome. Finally, treatment with phosphonoacetic acid or acyclovir prior to induction with PMA, anti-Ig, or TGF-β blocked the protective effect in Mutu-I cells. These data suggest that a late gene product(s) may be particularly important for protection against caspase activity and cell death.
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Xu, Jingwu, Ali Ahmad, and José Menezes. "Preferential Localization of the Epstein-Barr Virus (EBV) Oncoprotein LMP-1 to Nuclei in Human T Cells: Implications for Its Role in the Development of EBV Genome-Positive T-Cell Lymphomas." Journal of Virology 76, no. 8 (April 15, 2002): 4080–86. http://dx.doi.org/10.1128/jvi.76.8.4080-4086.2002.
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ABSTRACT The Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP-1) is thought to play a role in the EBV-induced B-cell transformation and immortalization. EBV has also been implicated in certain human T-cell lymphomas; however, the phenotypic effects of the expression of this oncoprotein in T cells are not known. To learn whether LMP-1 also induces phenotypic changes in T cells, we stably expressed it in human cell lines of T and B lineages and 25 LMP-1-expressing T-cell clones and 7 B-cell clones were examined. Our results show for the first time that, in sharp contrast to B cells, LMP-1 preferentially localizes to nuclei in T cells and does not induce the phenotypic changes in these cells that it induces in B cells, does not associate with TRAF proteins, and does not arrest the cell cycle in the G2/M phase. A computer-assisted analysis revealed that LMP-1 lacks the canonical nuclear localization signal. Our results suggest that this oncoprotein may not play the same role in the lymphomagenesis of T cells as it does in B cells.
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Majerciak, Vladimir, Natalia Pripuzova, J. Philip McCoy, Shou-Jiang Gao, and Zhi-Ming Zheng. "Targeted Disruption of Kaposi's Sarcoma-Associated Herpesvirus ORF57 in the Viral Genome Is Detrimental for the Expression of ORF59, K8α, and K8.1 and the Production of Infectious Virus." Journal of Virology 81, no. 3 (November 15, 2006): 1062–71. http://dx.doi.org/10.1128/jvi.01558-06.
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ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 regulates viral gene expression at the posttranscriptional level during viral lytic infection. To study its function in the context of the viral genome, we disrupted KSHV ORF57 in the KSHV genome by transposon-based mutagenesis. The insertion of the transposon into the ORF57 exon 2 region also interrupted the 3′ untranslated region of KSHV ORF56, which overlaps with the ORF57 coding region. The disrupted viral genome, Bac36-Δ57, did not express ORF57, ORF59, K8α, K8.1, or a higher level of polyadenylated nuclear RNA after butyrate induction and could not be induced to produce infectious viruses in the presence of valproic acid, a histone deacetylase inhibitor and a novel KSHV lytic cycle inducer. The ectopic expression of ORF57 partially complemented the replication deficiency of the disrupted KSHV genome and the expression of the lytic gene ORF59. The induced production of infectious virus particles from the disrupted KSHV genome was also substantially restored by the simultaneous expression of both ORF57 and ORF56; complementation by ORF57 alone only partially restored the production of virus, and expression of ORF56 alone showed no effect. Altogether, our data indicate that in the context of the viral genome, KSHV ORF57 is essential for ORF59, K8α, and K8.1 expression and infectious virus production.
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Noe, Katherine H., Cristina Cenciarelli, Sue A. Moyer, Paul A. Rota, and Moon L. Shin. "Requirements for Measles Virus Induction of RANTES Chemokine in Human Astrocytoma-Derived U373 Cells." Journal of Virology 73, no. 4 (April 1, 1999): 3117–24. http://dx.doi.org/10.1128/jvi.73.4.3117-3124.1999.
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ABSTRACT Interferons and chemokines play a critical role in regulating the host response to viral infection. Measles virus, a member of theParamyxoviridae family, induces RANTES expression by astrocytes. We have examined the mechanism of this induction in U373 cells derived from a human astrocytoma. RANTES was induced in a dose- and time-dependent manner by measles virus infection. Inhibition of receptor binding by the anti-CD46 antibody TRA-2.10 and of virus-membrane fusion by the tripeptide X-Phe-Phe-Gly reduced RANTES expression. Formalin-inactivated virus, which can bind but not fuse, and extensively UV-irradiated virus, which can bind and fuse, were both ineffective. Therefore, virus binding to the cellular receptor CD46 and subsequent membrane fusion were necessary, but not sufficient, to induce RANTES. UV irradiation of virus for less than 10 min proportionally inhibited viral transcription and RANTES expression. RANTES induction was decreased in infected cells treated with ribavirin, which inhibits measles virus transcription. However, RANTES mRNA was superinduced by measles virus in the presence of cycloheximide. These data suggest that partial transcription of the viral genome is sufficient and necessary for RANTES induction, whereas viral protein synthesis and replication are not required. This hypothesis was supported by the fact that RANTES was induced through transient expression of the measles virus nucleocapsid gene but not by measles genes encoding P or L proteins or by leader RNA in A549 cells. Thus, transcription of specific portions of measles virus RNA, such as the nucleocapsid gene, appears able to generate the specific signaling required to induce RANTES gene expression.
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Garnier, Olivier, Vincent Serrano, Sandra Duharcourt, and Eric Meyer. "RNA-Mediated Programming of Developmental Genome Rearrangements in Paramecium tetraurelia." Molecular and Cellular Biology 24, no. 17 (September 1, 2004): 7370–79. http://dx.doi.org/10.1128/mcb.24.17.7370-7379.2004.
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ABSTRACT The germ line genome of ciliates is extensively rearranged during development of the somatic macronucleus. Numerous sequences are eliminated, while others are amplified to a high ploidy level. In the Paramecium aurelia group of species, transformation of the maternal macronucleus with transgenes at high copy numbers can induce the deletion of homologous genes in sexual progeny, when a new macronucleus develops from the wild-type germ line. We show that this trans-nuclear effect correlates with homology-dependent silencing of maternal genes before autogamy and with the accumulation of ∼22- to 23-nucleotide (nt) RNA molecules. The same effects are induced by feeding cells before meiosis with bacteria containing double-stranded RNA, suggesting that small interfering RNA-like molecules can target deletions. Furthermore, experimentally induced macronuclear deletions are spontaneously reproduced in subsequent sexual generations, and reintroduction of the missing gene into the variant macronucleus restores developmental amplification in sexual progeny. We discuss the possible roles of the ∼22- to 23-nt RNAs in the targeting of deletions and the implications for the RNA-mediated genome-scanning process that is thought to determine developmentally regulated rearrangements in ciliates.
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Kennedy, P. G., O. Narayan, Z. Ghotbi, J. Hopkins, H. E. Gendelman, and J. E. Clements. "Persistent expression of Ia antigen and viral genome in visna-maedi virus-induced inflammatory cells. Possible role of lentivirus-induced interferon." Journal of Experimental Medicine 162, no. 6 (December 1, 1985): 1970–82. http://dx.doi.org/10.1084/jem.162.6.1970.
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In this study we investigated the pathogenesis of the lymphoproliferative response in the chronic-active visna maedi virus-induced inflammatory lesions. Viral RNA expression was confined to macrophages, but only in tissues showing inflammatory lesions. A persistent and high level of Ia antigen expression was seen in macrophage-like cells in the inflammatory lesions, and the amounts of viral RNA and Ia expression were closely correlated. A small subpopulation of macrophages contained both viral RNA and Ia antigen, and these were found in greatest number in the lung. In vitro experiments showed that a lentivirus-induced interferon (LV-IFN) could induce Ia antigens in normal sheep spleen and lymph node cells as well as in a transformed sheep macrophage cell line. Ia antigen expression in macrophages was transient in the absence of a continuing IFN stimulus and persisted for at least 2 wk in the presence of LV-IFN. LV-IFN also restricted viral replication in macrophages. It is suggested that LV-IFN induced by the inflammatory cells in visna-maedi lesions may induce Ia antigen expression in macrophages, thereby indirectly causing the lymphoproliferative response and restricted virus replication.
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Félix, Samuel R., Daiane D. Hartwig, Ana Paula C. Argondizzo, Éverton F. Silva, Fabiana K. Seixas, Amilton C. P. Seixas Neto, Marco A. Medeiros, Walter Lilenbaum, and Odir A. Dellagostin. "Subunit Approach to Evaluation of the Immune Protective Potential of Leptospiral Antigens." Clinical and Vaccine Immunology 18, no. 12 (October 26, 2011): 2026–30. http://dx.doi.org/10.1128/cvi.05297-11.
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ABSTRACTLeptospirosis is the most widespread zoonosis in the world. Current vaccines are based on whole-cell preparations that cause severe side effects and do not induce satisfactory immunity. In light of the leptospiral genome sequences recently made available, several studies aimed at identification of protective recombinant immunogens have been performed; however, few such immunogens have been identified. The aim of this study was to evaluate 27 recombinant antigens to determine their potential to induce an immune response protective against leptospirosis in the hamster model. Experiments were conducted with groups of female hamsters immunized with individual antigen preparations. Hamsters were then challenged with a lethal dose ofLeptospira interrogans. Thirteen antigens induced protective immune responses; however, only recombinant proteins LIC10325 and LIC13059 induced significant protection against mortality. These results have important implications for the development of an efficacious recombinant subunit vaccine against leptospirosis.
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Oh, Youngbin, Hyeonjin Kim, and Sang-Gyu Kim. "Virus-induced plant genome editing." Current Opinion in Plant Biology 60 (April 2021): 101992. http://dx.doi.org/10.1016/j.pbi.2020.101992.
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Paul, Sanjoy, Jennifer A. Schmidt, and W. Scott Moye-Rowley. "Regulation of the CgPdr1 Transcription Factor from the Pathogen Candida glabrata." Eukaryotic Cell 10, no. 2 (December 3, 2010): 187–97. http://dx.doi.org/10.1128/ec.00277-10.
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ABSTRACTCandida glabratais an opportunistic human pathogen that is increasingly associated with candidemia, owing in part to the intrinsic and acquired high tolerance the organism exhibits for the important clinical antifungal drug fluconazole. This elevated fluconazole resistance often develops through gain-of-function mutations in the zinc cluster-containing transcriptional regulatorC. glabrataPdr1 (CgPdr1). CgPdr1 induces the expression of an ATP-binding cassette (ABC) transporter-encoding gene, CgCDR1.Saccharomyces cerevisiaehas two CgPdr1 homologues called ScPdr1 and ScPdr3. These factors control the expression of an ABC transporter-encoding gene called ScPDR5, which encodes a homologue of CgCDR1. Loss of the mitochondrial genome (ρ0cell) or overexpression of the mitochondrial enzyme ScPsd1 induces ScPDR5expression in a strictly ScPdr3-dependent fashion. ScPdr3 requires the presence of a transcriptional Mediator subunit called Gal11 (Med15) to fully induce ScPDR5transcription in response to ρ0signaling. ScPdr1 does not respond to either ρ0signals or ScPsd1 overproduction. In this study, we employed transcriptional fusions between CgPdr1 target promoters, like CgCDR1, to demonstrate that CgPdr1 stimulates gene expression via binding to elements called pleiotropic drug response elements (PDREs). Deletion mapping and electrophoretic mobility shift assays demonstrated that a single PDRE in the CgCDR1promoter was capable of supporting ρ0-induced gene expression. Removal of one of the two ScGal11 homologues fromC. glabratacaused a major defect in drug-induced expression of CgCDR1but had a quantitatively minor effect on ρ0-stimulated transcription. These data demonstrate that CgPdr1 appears to combine features of ScPdr1 and ScPdr3 to produce a transcription factor with chimeric regulatory properties.
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Kreppel, Florian, and Claudia Hagedorn. "Capsid and Genome Modification Strategies to Reduce the Immunogenicity of Adenoviral Vectors." International Journal of Molecular Sciences 22, no. 5 (February 28, 2021): 2417. http://dx.doi.org/10.3390/ijms22052417.
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Adenovirus-based gene transfer vectors are the most frequently used vector type in gene therapy clinical trials to date, and they play an important role as genetic vaccine candidates during the ongoing SARS-CoV-2 pandemic. Immediately upon delivery, adenovirus-based vectors exhibit multiple complex vector-host interactions and induce innate and adaptive immune responses. This can severely limit their safety and efficacy, particularly after delivery through the blood stream. In this review article we summarize two strategies to modulate Ad vector-induced immune responses: extensive genomic and chemical capsid modifications. Both strategies have shown beneficial effects in a number of preclinical studies while potential synergistic effects warrant further investigations.
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Kushnir, Anna S., David J. Davido, and Priscilla A. Schaffer. "Role of Nuclear Factor Y in Stress-Induced Activation of the Herpes Simplex Virus Type 1 ICP0 Promoter." Journal of Virology 84, no. 1 (October 14, 2009): 188–200. http://dx.doi.org/10.1128/jvi.01377-09.
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ABSTRACT Herpesviruses are characterized by the ability to establish lifelong latent infections and to reactivate periodically, leading to recurrent disease. The herpes simplex virus type 1 (HSV-1) genome is maintained in a quiescent state in sensory neurons during latency, which is characterized by the absence of detectable viral protein synthesis. Cellular factors induced by stress may act directly on promoters within the latent viral genome to induce the transcription of viral genes and trigger reactivation. In order to identify which viral promoters are induced by stress and elucidate the cellular mechanism responsible for the induction, we generated a panel of HSV-1 promoter-luciferase constructs and measured their response to heat shock. Of the promoters tested, those of ICP0 and ICP22 were the most strongly upregulated after heat shock. Microarray analysis of lytically infected cells supported the upregulation of ICP0 and ICP22 promoters by heat shock. Mutagenic analysis of the ICP0 promoter identified two regions necessary for efficient heat-induced promoter activity, both containing predicted nuclear factor Y (NF-Y) sites, at bases −708 and −75 upstream of the transcriptional start site. While gel shift analysis confirmed NF-Y binding to both sites, only the site at −708 was important for efficient heat-induced activity. Reverse transcription-PCR analysis of selected viral transcripts in the presence of dominant-negative NF-Y confirmed the requirement for NF-Y in the induction of the ICP0 but not the ICP22 promoter by heat shock in lytically infected cells. These findings suggest that the immediate-early ICP0 gene may be among the first genes to be induced during the early events in HSV-1 reactivation, that NF-Y is important for this induction, and that other factors induce the ICP22 promoter.
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Somberg, Monika, Xiaomin Zhao, Monika Fröhlich, Magnus Evander, and Stefan Schwartz. "Polypyrimidine Tract Binding Protein Induces Human Papillomavirus Type 16 Late Gene Expression by Interfering with Splicing Inhibitory Elements at the Major Late 5′ Splice Site, SD3632." Journal of Virology 82, no. 7 (January 23, 2008): 3665–78. http://dx.doi.org/10.1128/jvi.02140-07.
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ABSTRACT We have initiated a screen for cellular factors that can induce human papillomavirus type 16 (HPV-16) late gene expression in human cancer cells. We report that the overexpression of polypyrimidine tract binding protein (PTB), also known as heterologous nuclear ribonucleoprotein I (hnRNP I), induces HPV-16 late gene expression in cells transfected with subgenomic HPV-16 plasmids or with full-length HPV-16 genomes and in persistently HPV-16-infected cells. In contrast, other hnRNPs such as hnRNP B1/A2, hnRNP F, and hnRNP Q do not induce HPV-16 late gene expression. PTB activates SD3632, the only 5′ splice site on the HPV-16 genome that is used exclusively by late mRNAs. PTB interferes with splicing inhibitory sequences located immediately upstream and downstream of SD3632, thereby activating late gene expression. One AU-rich PTB-responsive element was mapped to a 198-nucleotide sequence located downstream of SD3632. The deletion of this element induced HPV-16 late gene expression in the absence of PTB. Our results suggest that the overexpression of PTB interferes with cellular factors that interact with the inhibitory sequences. One may speculate that an increase in PTB levels or a reduction in the concentration of a PTB antagonist is required for the activation of HPV-16 late gene expression during the viral life cycle.
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Mitra, Aninda, Saradha Venkatachalapathy, Prasuna Ratna, Yejun Wang, Doorgesh Sharma Jokhun, and G. V. Shivashankar. "Cell geometry dictates TNFα-induced genome response." Proceedings of the National Academy of Sciences 114, no. 20 (May 1, 2017): E3882—E3891. http://dx.doi.org/10.1073/pnas.1618007114.
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Cells in physiology integrate local soluble and mechanical signals to regulate genomic programs. Whereas the individual roles of these signals are well studied, the cellular responses to the combined chemical and physical signals are less explored. Here, we investigated the cross-talk between cellular geometry and TNFα signaling. We stabilized NIH 3T3 fibroblasts into rectangular anisotropic or circular isotropic geometries and stimulated them with TNFα and analyzed nuclear translocation of transcription regulators –NFκB (p65) and MKL and downstream gene-expression patterns. We found that TNFα induces geometry-dependent actin depolymerization, which enhances IκB degradation, p65 nuclear translocation, nuclear exit of MKL, and sequestration of p65 at the RNA-polymerase-II foci. Further, global transcription profile of cells under matrix-TNFα interplay reveals a geometry-dependent gene-expression pattern. At a functional level, we find cell geometry affects TNFα-induced cell proliferation. Our results provide compelling evidence that fibroblasts, depending on their geometries, elicit distinct cellular responses for the same cytokine.
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Han, Yan-Chuang, Yoon Lim, Michael D. Duffieldl, Hua Li, Jia Liu, Nimshitha Pavathuparambil Abdul Manaph, Miao Yang, Damien J. Keating, and Xin-Fu Zhou. "Direct Reprogramming of Mouse Fibroblasts to Neural Stem Cells by Small Molecules." Stem Cells International 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/4304916.
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Although it is possible to generate neural stem cells (NSC) from somatic cells by reprogramming technologies with transcription factors, clinical utilization of patient-specific NSC for the treatment of human diseases remains elusive. The risk hurdles are associated with viral transduction vectors induced mutagenesis, tumor formation from undifferentiated stem cells, and transcription factors-induced genomic instability. Here we describe a viral vector-free and more efficient method to induce mouse fibroblasts into NSC using small molecules. The small molecule-induced neural stem (SMINS) cells closely resemble NSC in morphology, gene expression patterns, self-renewal, excitability, and multipotency. Furthermore, the SMINS cells are able to differentiate into astrocytes, functional neurons, and oligodendrocytesin vitroandin vivo. Thus, we have established a novel way to efficiently induce neural stem cells (iNSC) from fibroblasts using only small molecules without altering the genome. Such chemical induction removes the risks associated with current techniques such as the use of viral vectors or the induction of oncogenic factors. This technique may, therefore, enable NSC to be utilized in various applications within clinical medicine.
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Causton, Helen C., Bing Ren, Sang Seok Koh, Christopher T. Harbison, Elenita Kanin, Ezra G. Jennings, Tong Ihn Lee, Heather L. True, Eric S. Lander, and Richard A. Young. "Remodeling of Yeast Genome Expression in Response to Environmental Changes." Molecular Biology of the Cell 12, no. 2 (February 2001): 323–37. http://dx.doi.org/10.1091/mbc.12.2.323.
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We used genome-wide expression analysis to explore how gene expression in Saccharomyces cerevisiae is remodeled in response to various changes in extracellular environment, including changes in temperature, oxidation, nutrients, pH, and osmolarity. The results demonstrate that more than half of the genome is involved in various responses to environmental change and identify the global set of genes induced and repressed by each condition. These data implicate a substantial number of previously uncharacterized genes in these responses and reveal a signature common to environmental responses that involves ∼10% of yeast genes. The results of expression analysis with MSN2/MSN4 mutants support the model that the Msn2/Msn4 activators induce the common response to environmental change. These results provide a global description of the transcriptional response to environmental change and extend our understanding of the role of activators in effecting this response.
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Tan, Yee-Joo, Burtram C. Fielding, Phuay-Yee Goh, Shuo Shen, Timothy H. P. Tan, Seng Gee Lim, and Wanjin Hong. "Overexpression of 7a, a Protein Specifically Encoded by the Severe Acute Respiratory Syndrome Coronavirus, Induces Apoptosis via a Caspase-Dependent Pathway." Journal of Virology 78, no. 24 (December 15, 2004): 14043–47. http://dx.doi.org/10.1128/jvi.78.24.14043-14047.2004.
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ABSTRACT Besides genes that are homologous to proteins found in other coronaviruses, the severe acute respiratory syndrome coronavirus genome also contains nine other potential open reading frames. Previously, we have characterized the expression and cellular localization of two of these “accessory” viral proteins, 3a (previously termed U274) and 7a (previously termed U122). In this study, we further examined whether they can induce apoptosis, which has been observed clinically. We showed that the overexpression of 7a, but not of 3a or the viral structural proteins, nucleocapsid, membrane, and envelope, induces apoptosis. 7a induces apoptosis via a caspase-dependent pathway and in cell lines derived from different organs, including lung, kidney, and liver.
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Chaudhary, Juhi, Alisha Alisha, Vacha Bhatt, Sonali Chandanshive, Nirbhay Kumar, Zahoor Mir, Ashwini Kumar, et al. "Mutation Breeding in Tomato: Advances, Applicability and Challenges." Plants 8, no. 5 (May 14, 2019): 128. http://dx.doi.org/10.3390/plants8050128.
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Induced mutagenesis is one of the most effective strategies for trait improvement without altering the well-optimized genetic background of the cultivars. In this review, several currently accessible methods such as physical, chemical and insertional mutagenesis have been discussed concerning their efficient exploration for the tomato crop improvement. Similarly, challenges for the adaptation of genome-editing, a newly developed technique providing an opportunity to induce precise mutation, have been addressed. Several efforts of genome-editing have been demonstrated in tomato and other crops, exploring its effectiveness and convenience for crop improvement. Descriptive data compiled here from such efforts will be helpful for the efficient exploration of technological advances. However, uncertainty about the regulation of genome-edited crops is still a significant concern, particularly when timely trait improvement in tomato cultivars is needed. In this regard, random approaches of induced mutagenesis are still promising if efficiently explored in breeding applications. Precise identification of casual mutation is a prerequisite for the molecular understanding of the trait development as well as its utilization for the breeding program. Recent advances in sequencing techniques provide an opportunity for the precise detection of mutagenesis-induced sequence variations at a large scale in the genome. Here, we reviewed several novel next-generation sequencing based mutation mapping approaches including Mutmap, MutChromeSeq, and whole-genome sequencing-based mapping which has enormous potential to accelerate the mutation breeding in tomato. The proper utilization of the existing well-characterized tomato mutant resources combined with novel mapping approaches would inevitably lead to rapid enhancement of tomato quality and yield. This article provides an overview of the principles and applications of mutagenesis approaches in tomato and discusses the current progress and challenges involved in tomato mutagenesis research.
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Legge, S. E., M. L. Hamshere, S. Ripke, A. F. Pardinas, J. I. Goldstein, E. Rees, A. L. Richards, et al. "Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia." Molecular Psychiatry 22, no. 10 (July 12, 2016): 1502–8. http://dx.doi.org/10.1038/mp.2016.97.
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Abstract The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.
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Karban, R., and Y. Chen. "Induced resistance in rice against insects." Bulletin of Entomological Research 97, no. 4 (July 24, 2007): 327–35. http://dx.doi.org/10.1017/s0007485307005056.
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AbstractVaccinations are the mainstay of western preventive medicine, and they have been used to protect some crops against disease and insect pests. We consider rice as a model for protection using induced resistance since it is one of the most important staple crops and there have been significant new developments in: cross-resistance among rice insects, chemical pathways involved in induced resistance, sequencing the rice genome and expression of genes conferring resistance against rice insect pests. Insect attack has been found to cause lesions that kill planthopper eggs and early stages of gall midges. Damaged plants released volatiles that made them less likely to be chosen by planthoppers and more attractive to parasitoids. Chemical elicitors have been developed for dicotyledonous plants and these can induce resistance in rice, although rice does not fit models developed to explain signalling in dicots. For example, salicylic acid did not increase in rice after infection by pathogens and did not appear to be the mobile signal for induced resistance against pathogens although it was involved in induced responses to phloem-feeding insects. Jasmonic acid acted as a signal in some induced responses to pathogens as well as chewing insects. Many of the genes associated with induced resistance in rice have recently been mapped, and techniques are being developed to incorporate them into the genome of cultivated varieties. Attempts to control insect pests of rice will affect interactions with pathogens, predators and parasites, and other organisms in this agroecosystem.
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Alloisio, Nicole, Clothilde Queiroux, Pascale Fournier, Petar Pujic, Philippe Normand, David Vallenet, Claudine Médigue, Masatoshi Yamaura, Kentaro Kakoi, and Ken-ichi Kucho. "The Frankia alni Symbiotic Transcriptome." Molecular Plant-Microbe Interactions® 23, no. 5 (May 2010): 593–607. http://dx.doi.org/10.1094/mpmi-23-5-0593.
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The actinobacteria Frankia spp. are able to induce the formation of nodules on the roots of a large spectrum of actinorhizal plants, where they convert dinitrogen to ammonia in exchange for plant photosynthates. In the present study, transcriptional analyses were performed on nitrogen-replete free-living Frankia alni cells and on Alnus glutinosa nodule bacteria, using whole-genome microarrays. Distribution of nodule-induced genes on the genome was found to be mostly over regions with high synteny between three Frankia spp. genomes, while nodule-repressed genes, which were mostly hypothetical and not conserved, were spread around the genome. Genes known to be related to nitrogen fixation were highly induced, nif (nitrogenase), hup2 (hydrogenase uptake), suf (sulfur-iron cluster), and shc (hopanoids synthesis). The expression of genes involved in ammonium assimilation and transport was strongly modified, suggesting that bacteria ammonium assimilation was limited. Genes involved in particular in transcriptional regulation, signaling processes, protein drug export, protein secretion, lipopolysaccharide, and peptidoglycan biosynthesis that may play a role in symbiosis were also identified. We also showed that this Frankia symbiotic transcriptome was highly similar among phylogenetically distant plant families Betulaceae and Myricaceae. Finally, comparison with rhizobia transcriptome suggested that F. alni is metabolically more active in symbiosis than rhizobia.
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Jenkins, Glenn, Kenneth J. O'Byrne, Benedict Panizza, and Derek J. Richard. "Genome Stability Pathways in Head and Neck Cancers." International Journal of Genomics 2013 (2013): 1–19. http://dx.doi.org/10.1155/2013/464720.
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Genomic instability underlies the transformation of host cells toward malignancy, promotes development of invasion and metastasis and shapes the response of established cancer to treatment. In this review, we discuss recent advances in our understanding of genomic stability in squamous cell carcinoma of the head and neck (HNSCC), with an emphasis on DNA repair pathways. HNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk, treatment response and outcomes. Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in gene expression, and is a hallmark of progression toward carcinoma. Variable functionality of an increasing spectrum of repair gene polymorphisms is associated with increased cancer risk, while aetiological factors such as human papillomavirus, tobacco and alcohol induce significantly different behaviour in induced malignancy, underpinned by differences in genomic stability. Targeted inhibition of signalling receptors has proven to be a clinically-validated therapy, and protein expression of other DNA repair and signalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis and treatment prediction. Development and expansion of current genomic stability models is furthering our understanding of HNSCC pathophysiology and uncovering new, promising treatment strategies.
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Cleves, Phillip A., Marie E. Strader, Line K. Bay, John R. Pringle, and Mikhail V. Matz. "CRISPR/Cas9-mediated genome editing in a reef-building coral." Proceedings of the National Academy of Sciences 115, no. 20 (April 25, 2018): 5235–40. http://dx.doi.org/10.1073/pnas.1722151115.
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Reef-building corals are critically important species that are threatened by anthropogenic stresses including climate change. In attempts to understand corals’ responses to stress and other aspects of their biology, numerous genomic and transcriptomic studies have been performed, generating a variety of hypotheses about the roles of particular genes and molecular pathways. However, it has not generally been possible to test these hypotheses rigorously because of the lack of genetic tools for corals. Here, we demonstrate efficient genome editing using the CRISPR/Cas9 system in the coral Acropora millepora. We targeted the genes encoding fibroblast growth factor 1a (FGF1a), green fluorescent protein (GFP), and red fluorescent protein (RFP). After microinjecting CRISPR/Cas9 ribonucleoprotein complexes into fertilized eggs, we detected induced mutations in the targeted genes using changes in restriction-fragment length, Sanger sequencing, and high-throughput Illumina sequencing. We observed mutations in ∼50% of individuals screened, and the proportions of wild-type and various mutant gene copies in these individuals indicated that mutation induction continued for at least several cell cycles after injection. Although multiple paralogous genes encoding green fluorescent proteins are present in A. millepora, appropriate design of the guide RNA allowed us to induce mutations simultaneously in more than one paralog. Because A. millepora larvae can be induced to settle and begin colony formation in the laboratory, CRISPR/Cas9-based gene editing should allow rigorous tests of gene function in both larval and adult corals.
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Ma, Xue-Feng, Peng Fang, and J. Perry Gustafson. "Polyploidization-induced genome variation in triticale." Genome 47, no. 5 (October 1, 2004): 839–48. http://dx.doi.org/10.1139/g04-051.
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Polyploidization-induced genome variation in triticale (× Triticosecale Wittmack) was investigated using both AFLP and RFLP analyses. The AFLP analyses were implemented with both EcoRI–MseI (E–M) and PstI–MseI (P–M) primer combinations, which, because of their relative differences in sensitivity to cytosine methylation, primarily amplify repetitive and low-copy sequences, respectively. The results showed that the genomic sequences in triticale involved a great degree of variation including both repetitive and low-copy sequences. The frequency of losing parental bands was much higher than the frequency of gaining novel bands, suggesting that sequence elimination might be a major force causing genome variation in triticale. In all cases, variation in E–M primer-amplified parental bands was more frequent in triticale than that using P–M primers, suggesting that repetitive sequences were more involved in variation than low-copy sequences. The data also showed that the wheat (Triticum spp.) genomes were relatively highly conserved in triticales, especially in octoploid triticales, whereas the rye (Secale cereale L.) genome consistently demonstrated a very high level of genomic sequence variation (68%–72%) regardless of the triticale ploidy levels or primers used. In addition, when a parental AFLP band was present in both wheat and rye, the tendency of the AFLP band to be present in triticale was much higher than when it was present in only one of the progenitors. Furthermore, the cDNA-probed RFLP analyses showed that over 97% of the wheat coding sequences were maintained in triticale, whereas only about 61.6% of the rye coding sequences were maintained, suggesting that the rye genome variation in triticale also involved a high degree of rye coding sequence changes. The data also suggested that concerted evolution might occur in the genomic sequences of triticale. In addition, the observed genome variation in wheat–rye addition lines was similar to that in triticale, suggesting that wheat–rye addition lines can be used to thoroughly study the genome evolution of polyploid triticale.Key words: wheat, rye, polyploid, genome evolution, sequence elimination.
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Sakofsky, Cynthia, Sandeep Ayyar, and Anna Malkova. "Break-Induced Replication and Genome Stability." Biomolecules 2, no. 4 (October 16, 2012): 483–504. http://dx.doi.org/10.3390/biom2040483.
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Zutterling, Caroline, Aibek Mursalimov, Ibtissam Talhaoui, Zhanat Koshenov, Zhiger Akishev, Amangeldy K. Bissenbaev, Gerard Mazon, et al. "Aberrant repair initiated by the adenine-DNA glycosylase does not play a role in UV-induced mutagenesis in Escherichia coli." PeerJ 6 (December 5, 2018): e6029. http://dx.doi.org/10.7717/peerj.6029.
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Background DNA repair is essential to counteract damage to DNA induced by endo- and exogenous factors, to maintain genome stability. However, challenges to the faithful discrimination between damaged and non-damaged DNA strands do exist, such as mismatched pairs between two regular bases resulting from spontaneous deamination of 5-methylcytosine or DNA polymerase errors during replication. To counteract these mutagenic threats to genome stability, cells evolved the mismatch-specific DNA glycosylases that can recognize and remove regular DNA bases in the mismatched DNA duplexes. The Escherichia coli adenine-DNA glycosylase (MutY/MicA) protects cells against oxidative stress-induced mutagenesis by removing adenine which is mispaired with 7,8-dihydro-8-oxoguanine (8oxoG) in the base excision repair pathway. However, MutY does not discriminate between template and newly synthesized DNA strands. Therefore the ability to remove A from 8oxoG•A mispair, which is generated via misincorporation of an 8-oxo-2′-deoxyguanosine-5′-triphosphate precursor during DNA replication and in which A is the template base, can induce A•T→C•G transversions. Furthermore, it has been demonstrated that human MUTYH, homologous to the bacterial MutY, might be involved in the aberrant processing of ultraviolet (UV) induced DNA damage. Methods Here, we investigated the role of MutY in UV-induced mutagenesis in E. coli. MutY was probed on DNA duplexes containing cyclobutane pyrimidine dimers (CPD) and pyrimidine (6–4) pyrimidone photoproduct (6–4PP). UV irradiation of E. coli induces Save Our Souls (SOS) response characterized by increased production of DNA repair enzymes and mutagenesis. To study the role of MutY in vivo, the mutation frequencies to rifampicin-resistant (RifR) after UV irradiation of wild type and mutant E. coli strains were measured. Results We demonstrated that MutY does not excise Adenine when it is paired with CPD and 6–4PP adducts in duplex DNA. At the same time, MutY excises Adenine in A•G and A•8oxoG mispairs. Interestingly, E. coli mutY strains, which have elevated spontaneous mutation rate, exhibited low mutational induction after UV exposure as compared to MutY-proficient strains. However, sequence analysis of RifR mutants revealed that the frequencies of C→T transitions dramatically increased after UV irradiation in both MutY-proficient and -deficient E. coli strains. Discussion These findings indicate that the bacterial MutY is not involved in the aberrant DNA repair of UV-induced DNA damage.
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Halasz, Peter, Gavan Holloway, and Barbara S. Coulson. "Death mechanisms in epithelial cells following rotavirus infection, exposure to inactivated rotavirus or genome transfection." Journal of General Virology 91, no. 8 (August 1, 2010): 2007–18. http://dx.doi.org/10.1099/vir.0.018275-0.
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Intestinal epithelial cell death following rotavirus infection is associated with villus atrophy and gastroenteritis. Roles for both apoptosis and necrosis in cytocidal activity within rotavirus-infected epithelial cells have been proposed. Additionally, inactivated rotavirus has been reported to induce diarrhoea in infant mice. We further examined the death mechanisms induced in epithelial cell lines following rotavirus infection or inactivated rotavirus exposure. Monolayer integrity changes in MA104, HT-29 and partially differentiated Caco-2 cells following inactivated rotavirus exposure or RRV or CRW-8 rotavirus infection paralleled cell metabolic activity and viability reductions. MA104 cell exposure to rotavirus dsRNA also altered monolayer integrity. Inactivated rotaviruses induced delayed cell function losses that were unrelated to apoptosis. Phosphatidylserine externalization, indicating early apoptosis, occurred in MA104 and HT-29 but not in partially differentiated Caco-2 cells by 11 h after infection. Rotavirus activation of phosphatidylinositol 3-kinase partially protected MA104 and HT-29 cells from early apoptosis. In contrast, activation of the stress-activated protein kinase JNK by rotavirus did not influence apoptosis induction in these cells. RRV infection produced DNA fragmentation, indicating late-stage apoptosis, in fully differentiated Caco-2 cells only. These studies show that the apoptosis initiation and cell death mechanism induced by rotavirus infection depend on cell type and degree of differentiation. Early stage apoptosis resulting from rotavirus infection is probably counter-balanced by virus-induced phosphatidylinositol 3-kinase activation. The ability of inactivated rotaviruses and rotavirus dsRNA to perturb monolayer integrity supports a potential role for these rotavirus components in disease pathogenesis.
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Ernst, Orna, Jing Sun, Bin Lin, Balaji Banoth, Michael G. Dorrington, Jonathan Liang, Benjamin Schwarz, et al. "A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation." Science Signaling 14, no. 694 (August 3, 2021): eabe0387. http://dx.doi.org/10.1126/scisignal.abe0387.
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Noncanonical inflammasome activation by cytosolic lipopolysaccharide (LPS) is a critical component of the host response to Gram-negative bacteria. Cytosolic LPS recognition in macrophages is preceded by a Toll-like receptor (TLR) priming signal required to induce transcription of inflammasome components and facilitate the metabolic reprograming that fuels the inflammatory response. Using a genome-scale arrayed siRNA screen to find inflammasome regulators in mouse macrophages, we identified the mitochondrial enzyme nucleoside diphosphate kinase D (NDPK-D) as a regulator of both noncanonical and canonical inflammasomes. NDPK-D was required for both mitochondrial DNA synthesis and cardiolipin exposure on the mitochondrial surface in response to inflammasome priming signals mediated by TLRs, and macrophages deficient in NDPK-D had multiple defects in LPS-induced inflammasome activation. In addition, NDPK-D was required for the recruitment of TNF receptor–associated factor 6 (TRAF6) to mitochondria, which was critical for reactive oxygen species (ROS) production and the metabolic reprogramming that supported the TLR-induced gene program. NDPK-D knockout mice were protected from LPS-induced shock, consistent with decreased ROS production and attenuated glycolytic commitment during priming. Our findings suggest that, in response to microbial challenge, NDPK-D–dependent TRAF6 mitochondrial recruitment triggers an energetic fitness checkpoint required to engage and maintain the transcriptional program necessary for inflammasome activation.
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Boerman, Nicholas A., Ursula K. Frei, and Thomas Lübberstedt. "Impact of Spontaneous Haploid Genome Doubling in Maize Breeding." Plants 9, no. 3 (March 17, 2020): 369. http://dx.doi.org/10.3390/plants9030369.
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Doubled haploid (DH) technology has changed the maize-breeding landscape in recent years. Traditionally, DH production requires the use of chemical doubling agents to induce haploid genome doubling and, subsequently, male fertility. These chemicals can be harmful to humans and the plants themselves, and typically result in a doubling rate of 10%–30%. Spontaneous genome doubling and male fertility of maize haploids, without using chemical doubling agents, have been observed to a limited extent, for nearly 70 years. Rates of spontaneous haploid genome doubling (SHGD) have ranged from less than 5% to greater than 50%. Recently, there has been increased interest to forgo chemical treatment and instead utilize this natural method of doubling. Genetic-mapping studies comprising worldwide germplasm have been conducted. Of particular interest has been the detection of large-effect quantitative trait loci (QTL) affecting SHGD. Having a single large-effect QTL with an additive nature provides flexibility for the method of introgression, such as marker-assisted backcrossing, marker-assisted gene pyramiding, and systematic design. Moreover, it allows implementation of new methodologies, such as haploid-inducer mediated genome editing (HI-edit) and promotion of alleles by genome editing. We believe the use of SHGD can further enhance the impact of DH technology in maize.