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translesion synthesis

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https://www.readbyqxmd.com/read/28534480/molecular-basis-for-primpol-recruitment-to-replication-forks-by-rpa
#1
Thomas A Guilliam, Nigel C Brissett, Aaron Ehlinger, Benjamin A Keen, Peter Kolesar, Elaine M Taylor, Laura J Bailey, Howard D Lindsay, Walter J Chazin, Aidan J Doherty
DNA damage and secondary structures can stall the replication machinery. Cells possess numerous tolerance mechanisms to complete genome duplication in the presence of such impediments. In addition to translesion synthesis (TLS) polymerases, most eukaryotic cells contain a multifunctional replicative enzyme called primase-polymerase (PrimPol) that is capable of directly bypassing DNA damage by TLS, as well as repriming replication downstream of impediments. Here, we report that PrimPol is recruited to reprime through its interaction with RPA...
May 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28531304/replication-studies-of-carboxymethylated-dna-lesions-in-human-cells
#2
Jun Wu, Pengcheng Wang, Lin Li, Nicole L Williams, Debin Ji, Walter J Zahurancik, Changjun You, Jianshuang Wang, Zucai Suo, Yinsheng Wang
Metabolic activation of some N-nitroso compounds (NOCs), an important class of DNA damaging agents, can induce the carboxymethylation of nucleobases in DNA. Very little was previously known about how the carboxymethylated DNA lesions perturb DNA replication in human cells. Here, we investigated the effects of five carboxymethylated DNA lesions, i.e. O6-CMdG, N6-CMdA, N4-CMdC, N3-CMdT and O4-CMdT on the efficiency and fidelity of DNA replication in HEK293T human embryonic kidney cells. We found that, while neither N6-CMdA nor N4-CMdC blocked DNA replication or induced mutations, N3-CMdT, O4-CMdT and O6-CMdG moderately blocked DNA replication and induced substantial frequencies of T→A (81%), T→C (68%) and G→A (6...
May 22, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28522541/a-novel-histone-crosstalk-pathway-important-for-regulation-of-uv-induced-dna-damage-repair-in-saccharomyces-cerevisiae
#3
Anna L Boudoures, Jacob J Pfeil, Elizabeth M Steenkiste, Rachel A Hoffman, Elizabeth A Bailey, Sara E Wilkes, Sarah K Higdon, Jeffrey S Thompson
Histone post-translational modifications play vital roles in a variety of nuclear processes, including DNA repair. It has been previously shown that histone H3K79 methylation is important for the cellular response to DNA damage caused by ultraviolet (UV) radiation, with evidence that specific methylation states play distinct roles in UV repair. Here we report that H3K79 methylation is reduced in response to UV exposure in Saccharomyces cerevisiae This reduction is specific to the dimethylated state, as trimethylation levels are minimally altered by UV exposure...
May 18, 2017: Genetics
https://www.readbyqxmd.com/read/28498946/overexpression-of-rev1-promotes-the-development-of-carcinogen-induced-intestinal-adenomas-via-accumulation-of-point-mutation-and-suppression-of-apoptosis-proportionally-to-the-rev1-expression-level
#4
Megumi Sasatani, Yang Xi, Junko Kajimura, Toshiyuki Kawamura, Jinlian Piao, Yuji Masuda, Hiroaki Honda, Kei Kubo, Takahiro Mikamoto, Hiromitsu Watanabe, Yanbin Xu, Hidehiko Kawai, Tsutomu Shimura, Asao Noda, Kanya Hamasaki, Yoichiro Kusunoki, Elena Karamfilova Zaharieva, Kenji Kamiya
Cancer development often involves mutagenic replication of damaged DNA by the error-prone translesion synthesis (TLS) pathway. Aberrant activation of this pathway plays a role in tumorigenesis by promoting genetic mutations. Rev1 controls the function of the TLS pathway, and Rev1 expression levels are associated with DNA damage induced cytotoxicity and mutagenicity. However, it remains unclear whether deregulated Rev1 expression triggers or promotes tumorigenesis in vivo. In this study, we generated a novel Rev1-overexpressing transgenic (Tg) mouse and characterized its susceptibility to tumorigenesis...
May 1, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28497687/eukaryotic-translesion-dna-synthesis-on-the-leading-and-lagging-strands-unique-detours-around-the-same-obstacle
#5
Mark Hedglin, Stephen J Benkovic
During S-phase, minor DNA damage may be overcome by DNA damage tolerance (DDT) pathways that bypass such obstacles, postponing repair of the offending damage to complete the cell cycle and maintain cell survival. In translesion DNA synthesis (TLS), specialized DNA polymerases replicate the damaged DNA, allowing stringent DNA synthesis by a replicative polymerase to resume beyond the offending damage. Dysregulation of this DDT pathway in human cells leads to increased mutation rates that may contribute to the onset of cancer...
May 12, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28490629/pharmacological-targeting-of-rad6-enzyme-mediated-translesion-synthesis-overcomes-resistance-to-platinum-based-drugs
#6
Matthew A Sanders, Brittany Haynes, Pratima Nangia-Makker, Lisa A Polin, Malathy P Shekhar
Platinum drug-induced crosslink repair requires the concerted activities of translesion synthesis (TLS), Fanconi anemia (FA) and homologous recombination repair pathways. The E2 ubiquitin-conjugating enzyme Rad6 is essential for TLS. Here, we show that Rad6 plays a universal role in platinum-based drug tolerance. Using a novel Rad6-selective small molecule inhibitor (SMI#9) targeting the Rad6 catalytic site, we demonstrate that SMI#9 potentiates the sensitivities of cancer cells with innate or acquired cisplatin or oxaliplatin resistance...
May 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28489578/inhibiting-translesion-dna-synthesis-as-an-approach-to-combat-drug-resistance-to-dna-damaging-agents
#7
Jung-Suk Choi, Seol Kim, Edward Motea, Anthony Berdis
Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using "click" chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA...
April 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28474855/chromatin-regulates-genome-targeting-with-cisplatin
#8
Emmanouil Zacharioudakis, Poonam Agarwal, Alexandra Bartoli, Nathan Abell, Lavaniya Kunalingam, Valérie Bergoglio, Blerta Xhemalce, Kyle M Miller, Raphaël Rodriguez
Cisplatin derivatives can form various types of DNA lesions (DNA-Pt) and trigger pleiotropic DNA damage responses. Here, we report a strategy to visualize DNA-Pt with high resolution, taking advantage of a novel azide-containing derivative of cisplatin we named APPA, a cellular pre-extraction protocol and the labeling of DNA-Pt by means of click chemistry in cells. Our investigation revealed that pretreating cells with the histone deacetylase (HDAC) inhibitor SAHA led to detectable clusters of DNA-Pt that colocalized with the ubiquitin ligase RAD18 and the replication protein PCNA...
May 5, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28472716/combined-loss-of-three-dna-damage-response-pathways-renders-c-elegans-intolerant-to-light
#9
Ivo van Bostelen, Marcel Tijsterman
Infliction of DNA damage initiates a complex cellular reaction - the DNA damage response - that involves both signaling and DNA repair networks with many redundancies and parallel pathways. Here, we reveal the three strategies that the simple multicellular eukaryote, C. elegans, uses to deal with DNA damage induced by light. Separately inactivating repair or replicative bypass of photo-lesions results in cellular hypersensitivity towards UV-light, but impeding repair of replication associated DNA breaks does not...
April 14, 2017: DNA Repair
https://www.readbyqxmd.com/read/28459528/the-a-rule-and-deletion-formation-during-abasic-and-oxidized-abasic-site-bypass-by-dna-polymerase-%C3%AE
#10
Daniel J Laverty, April M Averill, Sylvie Doublié, Marc M Greenberg
DNA polymerase θ (Pol θ) is implicated in various cellular processes including double-strand break repair and apurinic/apyrimidinic site bypass. Because Pol θ expression correlates with poor cancer prognosis, the ability of Pol θ to bypass the C4'-oxidized abasic site (C4-AP) and 2-deoxyribonolactone (L), which are generated by cytotoxic agents, is of interest. Translesion synthesis and subsequent extension by Pol θ past C4-AP or L and an abasic site (AP) or its tetrahydrofuran analogue (F) was examined...
May 1, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28458162/a-genetic-study-based-on-pcna-ubiquitin-fusions-reveals-no-requirement-for-pcna-polyubiquitylation-in-dna-damage-tolerance
#11
Judit Z Gervai, Judit Gálicza, Zoltán Szeltner, Judit Zámborszky, Dávid Szüts
Post-translational modifications of Proliferating Cell Nuclear Antigen (PCNA) play a key role in regulating the bypass of DNA lesions during DNA replication. PCNA can be monoubiquitylated at lysine 164 by the RAD6-RAD18 ubiquitin ligase complex. Through this modification, PCNA can interact with low fidelity Y family DNA polymerases to promote translesion synthesis. Monoubiquitylated PCNA can be polyubiquitylated on lysine 63 of ubiquitin by a further ubiquitin-conjugating complex. This modification promotes a template switching bypass process in yeast, while its role in higher eukaryotes is less clear...
April 14, 2017: DNA Repair
https://www.readbyqxmd.com/read/28440919/rev7-the-regulatory-subunit-of-pol%C3%AE-undergoes-uv-induced-and-cul4-dependent-degradation
#12
Audesh Bhat, Zhoushuai Qin, Guifen Wang, Wangyang Chen, Wei Xiao
In eukaryotic cells, Rev7 interacts with Rev3 and functions as a regulatory subunit of Polζ, a translesion DNA synthesis (TLS) polymerase. In addition to its role in TLS, mammalian Rev7, also known as Mad2B/Mad2L2, participates in multiple cellular activities including cell cycle progression and double-strand break repair through its interaction with several proteins. Here we show that in mammalian cells Rev7 undergoes ubiquitin/proteasome-mediated degradation upon UV irradiation in a time-dependent manner...
April 25, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28431926/multiple-repair-pathways-mediate-cellular-tolerance-to-resveratrol-induced-dna-damage
#13
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 19, 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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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