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translesion synthesis

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https://www.readbyqxmd.com/read/28431926/multiple-repair-pathways-mediate-cellular-tolerance-to-resveratrol-induced-dna-damage
#1
Ying Liu, Xiaohua Wu, Xiaoqing Hu, Ziyuan Chen, Hao Liu, Shunichi Takeda, Yong Qing
Resveratrol (RSV) has been reported to exert health benefits for the prevention and treatment of many diseases, including cancer. The anticancer mechanisms of RSV seem to be complex and may be associated with genotoxic potential. To better understand the genotoxic mechanisms, we used wild-type (WT) and a panel of isogenic DNA-repair deficient DT40 cell lines to identify the DNA damage effects and molecular mechanisms of cellular tolerance to RSV. Our results showed that RSV induced significant formation of γ-H2AX foci and chromosome aberrations (CAs) in WT cells, suggesting direct DNA damage effects...
April 18, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28431012/replication-and-repair-of-a-reduced-2%C3%AE-deoxyguanosine-abasic-site-interstrand-cross-link-in-human-cells
#2
Nathan E Price, Lin Li, Kent S Gates, Yinsheng Wang
Apurinic/apyrimidinic (AP) sites, or abasic sites, which are a common type of endogenous DNA damage, can forge interstrand DNA-DNA cross-links via reaction with the exocyclic amino group on a nearby 2΄-deoxyguanosine or 2΄-deoxyadenosine in the opposite strand. Here, we utilized a shuttle vector method to examine the efficiency and fidelity with which a reduced dG-AP cross-link-containing plasmid was replicated in cultured human cells. Our results showed that the cross-link constituted strong impediments to DNA replication in HEK293T cells, with the bypass efficiencies for the dG- and AP-containing strands being 40% and 20%, respectively...
April 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28430587/parkin-regulates-translesion-dna-synthesis-in-response-to-uv-radiation
#3
Xuefei Zhu, Xiaolu Ma, Yingfeng Tu, Min Huang, Hongmei Liu, Fengli Wang, Juanjuan Gong, Jiuqiang Wang, Xiaoling Li, Qian Chen, Hongyan Shen, Shu Zhu, Yun Wang, Yang Liu, Caixia Guo, Tie-Shan Tang
Deficiency of Parkin is a major cause of early-onset Parkinson's disease (PD). Notably, PD patients also exhibit a significantly higher risk in melanoma and other skin tumors, while the mechanism remains largely unknown. In this study, we show that depletion of Parkin causes compromised cell viability and genome stability after ultraviolet (UV) radiation. We demonstrate that Parkin promotes efficient Rad18-dependent proliferating cell nuclear antigen (PCNA) monoubiquitination by facilitating the formation of Replication protein A (RPA)-coated ssDNA upon UV radiation...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28402640/mutagenic-replication-of-n-2-deoxyguanosine-benzo-a-pyrene-adducts-by-escherichia-coli-dna-polymerase-i-and-sulfolobus-solfataricus-dna-polymerase-iv
#4
A S Prakasha Gowda, Jacek Krzeminski, Shantu Amin, Zucai Suo, Thomas E Spratt
Benzo[a]pyrene, a potent human carcinogen, is metabolized in vivo to a diol epoxide that reacts with the N(2)-position of guanine to produce N(2)-BP-dG adducts. These adducts are mutagenic causing G to T transversions. These adducts block replicative polymerases but can be bypassed by the Y-family translesion synthesis polymerases. The mechanisms by which mutagenic bypass occurs is not well-known. We have evaluated base pairing structures using atomic substitution of the dNTP with two stereoisomers, 2'-deoxy-N-[(7R,8S,9R,10S)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine and 2'-deoxy-N-[(7S,8R,9S,10R)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine...
April 19, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28395138/formation-of-s-2-n-6-deoxyadenosinyl-ethyl-glutathione-in-dna-and-replication-past-the-adduct-by-translesion-dna-polymerases
#5
Carl A Sedgeman, Yan Su, F Peter Guengerich
1,2-Dibromoethane (DBE, ethylene dibromide) is a potent carcinogen due at least in part to its DNA cross-linking effects. DBE cross-links glutathione (GSH) to DNA, notably to sites on 2'-deoxyadenosine and 2'-deoxyguanosine ( Cmarik , J. L. , et al. ( 1991 ) J. Biol. Chem. 267 , 6672 - 6679 ). Adduction at the N6 position of 2'-deoxyadenosine (dA) had not been detected, but this is a site for the linkage of O(6)-alkylguanine DNA alkyltransferase ( Chowdhury , G. , et al. ( 2013 ) Angew. Chem. Int. Ed. 52 , 12879 - 12882 )...
April 14, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28394575/1-3-butadiene-induced-adenine-dna-adducts-are-genotoxic-but-only-weakly-mutagenic-when-replicated-in-escherichia-coli-of-various-repair-and-replication-backgrounds
#6
Shiou-Chi Chang, Uthpala I Seneviratne, Jie Wu, Natalia Tretyakova, John M Essigmann
The adverse effects of the human carcinogen 1,3-butadiene (BD) are believed to be mediated by its DNA-reactive metabolites such as 3,4-epoxybut-1-ene (EB) and 1,2,3,4-diepoxybutane (DEB). The specific DNA adducts responsible for toxic and mutagenic effects of BD, however, have yet to be identified. Recent in vitro polymerase bypass studies of BD-induced adenine (BD-dA) adducts show that DEB-induced N(6),N(6)-DHB-dA (DHB = 2,3-dihydroxybutan-1,4-diyl) and 1,N(6)-γ-HMHP-dA (HMHP = 2-hydroxy-3-hydroxymethylpropan-1,3-diyl) adducts block replicative DNA polymerases but are bypassed by human polymerases η and κ, leading to point mutations and deletions...
April 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28391554/translesion-synthesis-dna-polymerase-kappa-is-indispensable-for-dna-repair-synthesis-in-cisplatin-exposed-dorsal-root-ganglion-neurons
#7
Ming Zhuo, Murat F Gorgun, Ella W Englander
In the peripheral nervous system (PNS) in the absence of tight blood barrier, neurons are at increased risk of DNA damage, yet the question of how effectively PNS neurons manage DNA damage remains largely unanswered. Genotoxins in systemic circulation include chemotherapeutic drugs that reach peripheral neurons and damage their DNA. Because neurotoxicity of platinum-based class of chemotherapeutic drugs has been implicated in PNS neuropathies, we utilized an in vitro model of Dorsal Root Ganglia (DRGs) to investigate how peripheral neurons respond to cisplatin that forms intra- and interstrand crosslinks with their DNA...
April 8, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28388097/replicative-bypass-studies-of-%C3%AE-anomeric-lesions-of-2-deoxyribonucleosides-in-vitro
#8
Nicole L Williams, Nicholas J Amato, Yinsheng Wang
Genomic integrity is constantly challenged by a variety of endogenous and exogenous DNA damaging agents, which can lead to the formation of 10(4)-10(5) DNA lesions per cell per day. Reactive oxygen species (ROS) represent a major type of DNA damaging agent. Specifically, a hydroxyl radical can attack the C1' position of 2-deoxyribose, and the ensuing carbon-centered radical, if improperly repaired, can cause the inversion of stereochemical configuration at the C1' to give α-anomeric lesions. In this study, we assessed the replicative bypass of α-dA, α-dT, α-dC, and α-dG in template DNA by conducting primer extension assays with the use of purified translesion synthesis DNA polymerases...
April 14, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28383109/simulating-the-fidelity-and-the-three-mg-mechanism-of-pol-%C3%AE-and-clarifying-the-validity-of-transition-state-theory-in-enzyme-catalysis
#9
Hanwool Yoon, Arieh Warshel
Pol η belongs to the important Y family of DNA polymerases that can catalyze translesion synthesis across sites of damaged DNA. This activity involves the reduced fidelity of Pol η for 8-oxo-7,8-dhyedro-2'-deoxoguanosin(8-oxoG). The fundamental interest in Pol η has grown recently with the demonstration of the importance of a 3(rd) Mg(2+) ion. The current work explores both the fidelity of Pol η and the role of the 3(rd) metal ion, by using empirical valence bond (EVB) simulations. The simulations reproduce the observed trend in fidelity and shed a new light on the role of the 3(rd) metal ion...
April 6, 2017: Proteins
https://www.readbyqxmd.com/read/28380422/the-dominant-role-of-proofreading-exonuclease-activity-of-replicative-polymerase-%C3%AE%C2%B5-in-cellular-tolerance-to-cytarabine-ara-c
#10
Masataka Tsuda, Kazuhiro Terada, Masato Ooka, Koji Kobayashi, Hiroyuki Sasanuma, Ryo Fujisawa, Toshiki Tsurimoto, Junpei Yamamoto, Shigenori Iwai, Kei Kadoda, Remi Akagawa, Shar-Yin Naomi Huang, Yves Pommier, Julian E Sale, Shunichi Takeda, Kouji Hirota
Chemotherapeutic nucleoside analogs, such as Ara-C, 5-Fluorouracil (5-FU) and Trifluridine (FTD), are frequently incorporated into DNA by the replicative DNA polymerases. However, it remains unclear how this incorporation kills cycling cells. There are two possibilities: Nucleoside analog triphosphates inhibit the replicative DNA polymerases, and/or nucleotide analogs mis-incorporated into genomic DNA interfere with the next round of DNA synthesis as replicative DNA polymerases recognize them as template DNA lesions, arresting synthesis...
March 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28369478/a-non-catalytic-role-of-recbcd-in-homology-directed-gap-repair-and-translesion-synthesis
#11
Luisa Laureti, Lara Lee, Gaëlle Philippin, Vincent Pagès
The RecBCD complex is a key factor in DNA metabolism. This protein complex harbors a processive nuclease and two helicases activities that give it the ability to process duplex DNA ends. These enzymatic activities make RecBCD a major player in double strand break repair, conjugational recombination and degradation of linear DNA. In this work, we unravel a new role of the RecBCD complex in the processing of DNA single-strand gaps that are generated at DNA replication-blocking lesions. We show that independently of its nuclease or helicase activities, the entire RecBCD complex is required for recombinational repair of the gap and efficient translesion synthesis...
March 29, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28348081/the-herpes-simplex-virus-1-ul36usp-deubiquitinase-suppresses-dna-repair-in-host-cells-via-deubiquitination-of-proliferating-cell-nuclear-antigen
#12
Xiaodong Dong, Junhong Guan, Chunfu Zheng, Xiaofeng Zheng
Herpes simplex virus 1 (HSV-1) infection manipulates distinct host DNA damage responses (DDR) to facilitate virus proliferation, but the molecular mechanisms remain to be elucidated. One possible HSV-1 target might be DNA damage-tolerance mechanisms, such as the translesion synthesis (TLS) pathway. In TLS, proliferating cell nuclear antigen (PCNA) is monoubiquitinated in response to DNA damage-caused replication fork stalling. Ubiquitinated PCNA then facilitates the error-prone DNA polymerase eta (pol eta)-mediated TLS, allowing the fork to bypass damaged sites...
March 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28341648/dna-damage-tolerance-pathway-choice-through-uls1-modulation-of-srs2-sumoylation-in-saccharomyces-cerevisiae
#13
Karol Kramarz, Seweryn Mucha, Ireneusz Litwin, Anna Barg-Wojas, Robert Wysocki, Dorota Dziadkowiec
DNA damage tolerance and homologous recombination pathways function to bypass replication blocking lesions and ensure completion of DNA replication. However, inappropriate activation of these pathways may lead to increased mutagenesis or formation of deleterious recombination intermediates often leading to cell death or cancer formation in higher organisms. Posttranslational modifications of PCNA regulate the choice of repair pathways at replication forks. Its monoubiquitination favors translesion synthesis while polyubiquitination stimulates template switching...
March 24, 2017: Genetics
https://www.readbyqxmd.com/read/28334887/avoidance-of-apobec3b-induced-mutation-by-error-free-lesion-bypass
#14
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
#15
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
#16
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
#17
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
#18
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...
March 14, 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
#19
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
#20
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