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translesion synthesis

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https://www.readbyqxmd.com/read/28334887/avoidance-of-apobec3b-induced-mutation-by-error-free-lesion-bypass
#1
James I Hoopes, Amber L Hughes, Lauren A Hobson, Luis M Cortez, Alexander J Brown, Steven A Roberts
APOBEC cytidine deaminases mutate cancer genomes by converting cytidines into uridines within ssDNA during replication. Although uracil DNA glycosylases limit APOBEC-induced mutation, it is unknown if subsequent base excision repair (BER) steps function on replication-associated ssDNA. Hence, we measured APOBEC3B-induced CAN1 mutation frequencies in yeast deficient in BER endonucleases or DNA damage tolerance proteins. Strains lacking Apn1, Apn2, Ntg1, Ntg2 or Rev3 displayed wild-type frequencies of APOBEC3B-induced canavanine resistance (CanR)...
March 10, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28290677/molecular-insights-into-the-translesion-synthesis-of-benzyl-guanine-from-molecular-dynamics-simulations-structural-evidence-of-mutagenic-and-nonmutagenic-replication
#2
Katie A Wilson, Stacey D Wetmore
DNA can be damaged by many compounds in our environment, and the resulting damaged DNA is commonly replicated by translesion synthesis (TLS) polymerases. Because the mechanism and efficiency of TLS are affected by the type of DNA damage, obtaining information for a variety of DNA adducts is critical. However, there is no structural information for the insertion of a dNTP opposite an O6-dG adduct, which is a particularly harmful class of DNA lesions. We used molecular dynamics (MD) simulations to investigate structural and energetic parameters that dictate preferred dNTP insertion opposite O6-benzyl-guanine (Bz-dG) by DNA polymerase IV, a prototypical TLS polymerase...
March 24, 2017: Biochemistry
https://www.readbyqxmd.com/read/28279077/translesion-dna-polymerases-in-eukaryotes-what-makes-them-tick
#3
Alexandra Vaisman, Roger Woodgate
Life as we know it, simply would not exist without DNA replication. All living organisms utilize a complex machinery to duplicate their genomes and the central role in this machinery belongs to replicative DNA polymerases, enzymes that are specifically designed to copy DNA. "Hassle-free" DNA duplication exists only in an ideal world, while in real life, it is constantly threatened by a myriad of diverse challenges. Among the most pressing obstacles that replicative polymerases often cannot overcome by themselves are lesions that distort the structure of DNA...
March 9, 2017: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28273172/altering-the-n-terminal-arms-of-the-polymerase-manager-protein-umud-modulates-protein-interactions
#4
David A Murison, Jaylene N Ollivierre, Qiuying Huang, David E Budil, Penny J Beuning
Escherichia coli cells that are exposed to DNA damaging agents invoke the SOS response that involves expression of the umuD gene products, along with more than 50 other genes. Full-length UmuD is expressed as a 139-amino-acid protein, which eventually cleaves its N-terminal 24 amino acids to form UmuD'. The N-terminal arms of UmuD are dynamic and contain recognition sites for multiple partner proteins. Cleavage of UmuD to UmuD' dramatically affects the function of the protein and activates UmuC for translesion synthesis (TLS) by forming DNA Polymerase V...
2017: PloS One
https://www.readbyqxmd.com/read/28246327/monoubiquitylation-of-histone-h2b-contributes-to-the-bypass-of-dna-damage-during-and-after-dna-replication
#5
Shih-Hsun Hung, Ronald P Wong, Helle D Ulrich, Cheng-Fu Kao
DNA lesion bypass is mediated by DNA damage tolerance (DDT) pathways and homologous recombination (HR). The DDT pathways, which involve translesion synthesis and template switching (TS), are activated by the ubiquitylation (ub) of PCNA through components of the RAD6-RAD18 pathway, whereas the HR pathway is independent of RAD18 However, it is unclear how these processes are coordinated within the context of chromatin. Here we show that Bre1, an ubiquitin ligase specific for histone H2B, is recruited to chromatin in a manner coupled to replication of damaged DNA...
February 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28223526/hypermutation-signature-reveals-a-slippage-and-realignment-model-of-translesion-synthesis-by-rev3-polymerase-in-cisplatin-treated-yeast
#6
Romulo Segovia, Yaoqing Shen, Scott A Lujan, Steven J M Jones, Peter C Stirling
Gene-gene or gene-drug interactions are typically quantified using fitness as a readout because the data are continuous and easily measured in high throughput. However, to what extent fitness captures the range of other phenotypes that show synergistic effects is usually unknown. Using Saccharomyces cerevisiae and focusing on a matrix of DNA repair mutants and genotoxic drugs, we quantify 76 gene-drug interactions based on both mutation rate and fitness and find that these parameters are not connected. Independent of fitness defects, we identified six cases of synthetic hypermutation, where the combined effect of the drug and mutant on mutation rate was greater than predicted...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28199639/rapid-evolution-of-acetic-acid-detoxifying-escherichia-coli-under-phosphate-starvation-conditions-requires-activation-of-the-cryptic-phne-permease-and-induction-of-translesion-synthesis-dna-polymerases
#7
https://www.readbyqxmd.com/read/28180309/predominant-role-of-dna-polymerase-eta-and-p53-dependent-translesion-synthesis-in-the-survival-of-ultraviolet-irradiated-human-cells
#8
Leticia K Lerner, Guilherme Francisco, Daniela T Soltys, Clarissa R R Rocha, Annabel Quinet, Alexandre T Vessoni, Ligia P Castro, Taynah I P David, Silvina O Bustos, Bryan E Strauss, Vanesa Gottifredi, Anne Stary, Alain Sarasin, Roger Chammas, Carlos F M Menck
No abstract text is available yet for this article.
February 17, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28177605/replication-protein-a-prohibits-diffusion-of-the-pcna-sliding-clamp-along-single-stranded-dna
#9
Mark Hedglin, Stephen J Benkovic
The replicative polymerases cannot accommodate distortions to the native DNA sequence such as modifications (lesions) to the native template bases from exposure to reactive metabolites and environmental mutagens. Consequently, DNA synthesis on an afflicted template abruptly stops upon encountering these lesions but the replication fork progresses onward, exposing long stretches of the damaged template before eventually stalling. Such arrests may be overcome by translesion DNA synthesis where a specialized TLS polymerases binds to the resident PCNA and replicates the damaged DNA...
February 8, 2017: Biochemistry
https://www.readbyqxmd.com/read/28118378/dna-polymerases-imuc-and-dinb-are-involved-in-dna-alkylation-damage-tolerance-in-pseudomonas-aeruginosa-and-pseudomonas-putida
#10
Tatjana Jatsenko, Julia Sidorenko, Signe Saumaa, Maia Kivisaar
Translesion DNA synthesis (TLS), facilitated by low-fidelity polymerases, is an important DNA damage tolerance mechanism. Here, we investigated the role and biological function of TLS polymerase ImuC (former DnaE2), generally present in bacteria lacking DNA polymerase V, and TLS polymerase DinB in response to DNA alkylation damage in Pseudomonas aeruginosa and P. putida. We found that TLS DNA polymerases ImuC and DinB ensured a protective role against N- and O-methylation induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in both P...
2017: PloS One
https://www.readbyqxmd.com/read/28109890/sunlight-damage-to-cellular-dna-focus-on-oxidatively-generated-lesions
#11
REVIEW
André Passaglia Schuch, Natália Cestari Moreno, Natielen Jacques Schuch, Carlos Frederico Martins Menck, Camila Carrião Machado Garcia
The routine and often unavoidable exposure to solar ultraviolet (UV) radiation makes it one of the most significant environmental DNA-damaging agents to which humans are exposed. Sunlight, specifically UVB and UVA, triggers various types of DNA damage. Although sunlight, mainly UVB, is necessary for the production of vitamin D, which is necessary for human health, DNA damage may have several deleterious consequences, such as cell death, mutagenesis, photoaging and cancer. UVA and UVB photons can be directly absorbed not only by DNA, which results in lesions, but also by the chromophores that are present in skin cells...
January 18, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28092942/advances-in-structural-and-single-molecule-methods-for-investigating-dna-lesion-bypass-and-repair-polymerases
#12
Austin T Raper, Andrew J Reed, Varun V Gadkari, Zucai Suo
Innovative advances in X-ray crystallography and single-molecule biophysics have yielded unprecedented insight into the mechanisms of DNA lesion bypass and damage repair. Time-dependent X-ray crystallography has been successfully applied to view the bypass of 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxoG), a major oxidative DNA lesion, and the incorporation of the triphosphate form, 8-oxo-dGTP, catalyzed by human DNA polymerase β. Significant findings of these studies are highlighted here, and their contributions to the current mechanistic understanding of mutagenic translesion DNA synthesis (TLS) and base excision repair are discussed...
January 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28077981/dna-polymerase-kappa-protects-human-cells-against-mmc-induced-genotoxicity-through-error-free-translesion-dna-synthesis
#13
Yuki Kanemaru, Tetsuya Suzuki, Akira Sassa, Kyomu Matsumoto, Noritaka Adachi, Masamitsu Honma, Satoshi Numazawa, Takehiko Nohmi
BACKGROUND: Interactions between genes and environment are critical factors for causing cancer in humans. The genotoxicity of environmental chemicals can be enhanced via the modulation of susceptible genes in host human cells. DNA polymerase kappa (Pol κ) is a specialized DNA polymerase that plays an important role in DNA damage tolerance through translesion DNA synthesis. To better understand the protective roles of Pol κ, we previously engineered two human cell lines either deficient in expression of Pol κ (KO) or expressing catalytically dead Pol κ (CD) in Nalm-6-MSH+ cells and examined cytotoxic sensitivity against various genotoxins...
2017: Genes and Environment: the Official Journal of the Japanese Environmental Mutagen Society
https://www.readbyqxmd.com/read/28077248/alternative-splicing-at-exon-2-results-in-the-loss-of-the-catalytic-activity-of-mouse-dna-polymerase-iota-in-vitro
#14
Konstantin Y Kazachenko, Nataliya A Miropolskaya, Leonid V Gening, Vyacheslav Z Tarantul, Alena V Makarova
Y-family DNA polymerase iota (Pol ι) possesses both DNA polymerase and dRP lyase activities and was suggested to be involved in DNA translesion synthesis and base excision repair in mammals. The 129 strain of mice and its derivatives have a natural nonsense codon mutation in the second exon of the Pol ι gene resulting in truncation of the Pol ι protein. These mice were widely used as a Pol ι-null model for in vivo studies of the Pol ι function. However whether 129-derived strains of mice are fully deficient in the Pol ι functions was a subject of discussion since Pol ι mRNA undergoes alternative splicing at exon 2...
February 2017: DNA Repair
https://www.readbyqxmd.com/read/28075396/translesion-synthesis-insights-into-the-selection-and-switching-of-dna-polymerases
#15
REVIEW
Linlin Zhao, M Todd Washington
DNA replication is constantly challenged by DNA lesions, noncanonical DNA structures and difficult-to-replicate DNA sequences. Two major strategies to rescue a stalled replication fork and to ensure continuous DNA synthesis are: (1) template switching and recombination-dependent DNA synthesis; and (2) translesion synthesis (TLS) using specialized DNA polymerases to perform nucleotide incorporation opposite DNA lesions. The former pathway is mainly error-free, and the latter is error-prone and a major source of mutagenesis...
January 10, 2017: Genes
https://www.readbyqxmd.com/read/28075014/knockdown-of-rev3-synergizes-with-atr-inhibition-to-promote-apoptosis-induced-by-cisplatin-in-lung-cancer-cells
#16
He-Guo Jiang, Ping Chen, Jin-Yu Su, Ming Wu, Hai Qian, Yi Wang, Jian Li
It has been demonstrated that REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase ζ, play an important role in DNA damage response (DDR) induced by cisplatin, and Ataxia telangietasia mutated and Rad-3-related (ATR) knase is a central player in activating cell cycle checkpoint, stabilizing replication forks, regulating DDR, and promoting repair of DNA damage caused by cisplatin. Cancer cells deficient in either one of REV3 and ATR are more sensitive to cisplatin. However, whether co-inhibition of REV3 and ATR can further increase sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin is not clear...
January 11, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28053116/dna-dependent-protease-activity-of-human-spartan-facilitates-replication-of-dna-protein-crosslink-containing-dna
#17
Mónika Mórocz, Eszter Zsigmond, Róbert Tóth, Márton Zs Enyedi, Lajos Pintér, Lajos Haracska
Mutations in SPARTAN are associated with early onset hepatocellular carcinoma and progeroid features. A regulatory function of Spartan has been implicated in DNA damage tolerance pathways such as translesion synthesis, but the exact function of the protein remained unclear. Here, we reveal the role of human Spartan in facilitating replication of DNA-protein crosslink-containing DNA. We found that purified Spartan has a DNA-dependent protease activity degrading certain proteins bound to DNA. In concert, Spartan is required for direct DPC removal in vivo; we also show that the protease Spartan facilitates repair of formaldehyde-induced DNA-protein crosslinks in later phases of replication using the bromodeoxyuridin (BrdU) comet assay...
January 3, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27994034/ribonucleotide-incorporation-by-human-dna-polymerase-%C3%AE-impacts-translesion-synthesis-and-rnase-h2-activity
#18
Elisa Mentegari, Emmanuele Crespan, Laura Bavagnoli, Miroslava Kissova, Federica Bertoletti, Simone Sabbioneda, Ralph Imhof, Shana J Sturla, Arman Nilforoushan, Ulrich Hübscher, Barbara van Loon, Giovanni Maga
Ribonucleotides (rNs) incorporated in the genome by DNA polymerases (Pols) are removed by RNase H2. Cytidine and guanosine preferentially accumulate over the other rNs. Here we show that human Pol η can incorporate cytidine monophosphate (rCMP) opposite guanine, 8-oxo-7,8-dihydroguanine, 8-methyl-2'-deoxyguanosine and a cisplatin intrastrand guanine crosslink (cis-PtGG), while it cannot bypass a 3-methylcytidine or an abasic site with rNs as substrates. Pol η is also capable of synthesizing polyribonucleotide chains, and its activity is enhanced by its auxiliary factor DNA Pol δ interacting protein 2 (PolDIP2)...
December 19, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27974823/roles-of-human-pold1-and-pold3-in-genome-stability
#19
Emanuela Tumini, Sonia Barroso, Carmen Pérez -Calero, Andrés Aguilera
DNA replication is essential for cellular proliferation. If improperly controlled it can constitute a major source of genome instability, frequently associated with cancer and aging. POLD1 is the catalytic subunit and POLD3 is an accessory subunit of the replicative Pol δ polymerase, which also functions in DNA repair, as well as the translesion synthesis polymerase Pol ζ, whose catalytic subunit is REV3L. In cells depleted of POLD1 or POLD3 we found a differential but general increase in genome instability as manifested by DNA breaks, S-phase progression impairment and chromosome abnormalities...
December 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27951635/mutagenicity-of-a-model-dna-peptide-cross-link-in-human-cells-roles-of-translesion-synthesis-dna-polymerases
#20
Paritosh Pande, Shaofei Ji, Shivam Mukherjee, Orlando D Schärer, Natalia Y Tretyakova, Ashis K Basu
DNA-protein cross-links are formed upon exposure of cellular DNA to various agents, including antitumor drugs, UV light, transition metals, and reactive oxygen species. They are thought to contribute to cancer, aging, and neurodegenerative diseases. It has been proposed that DNA-protein cross-links formed in cells are subject to proteolytic degradation to the corresponding DNA-peptide cross-links (DpCs). To investigate the effects of DpCs on DNA replication, we have constructed plasmid DNA containing a 10-mer Myc peptide covalently linked to C7 of 7-deaza-dG, a hydrolytically stable mimic of N7-dG lesions...
February 20, 2017: Chemical Research in Toxicology
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