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translesion synthesis

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https://www.readbyqxmd.com/read/28724765/translesion-polymerase-pol-%C3%AE-is-required-for-efficient-epstein-barr-virus-infectivity-and-is-regulated-by-the-viral-deubiquitinating-enzyme-bplf1
#1
Ossie F Dyson, Joseph S Pagano, Christopher B Whitehurst
Epstein-Barr Virus (EBV) infection and lytic replication are known to induce a cellular DNA damage response. Previously we showed that the virally encoded BPLF1 protein interacts with and regulates several members of the translesion synthesis pathway (TLS), a DNA damage tolerance pathway, and that these cellular factors enhance viral infectivity. BPLF1 is a late lytic cycle gene, but the protein is also packaged in the viral tegument indicating that BPLF1 may function both early and late during infection. BPLF1 expresses deubiquitinating activity that is strictly conserved across the Herpesviridae; mutation of the active-site cysteine results in loss of enzymatic activity...
July 19, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28710267/increased-processivity-misincorporation-and-nucleotide-incorporation-efficiency-in-sulfolobus-solfataricus-dpo4-thumb-domain-mutations
#2
Li Wang, Chenchen Liang, Jing Wu, Liming Liu, Keith E J Tyo
The present study aimed to increase the processivity of Sulfolobus solfataricus DNA polymerase Dpo4. Protein engineering and bioinformatics were used to compile a library of potential Dpo4 mutation sites. Ten potential mutants were identified and constructed. A primer extension assay was used to evaluate the processivity of Dpo4 mutants. Thumb (A181D) and finger (E63K) domain mutants showed a processivity of 20 and 19 nucleotides (nt), respectively. A little finger domain mutant (I248Y) exhibited a processivity of 17 nt, only 1 nt more than wild-type Dpo4...
July 14, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28668126/analyzing-the-catalytic-activities-and-interactions-of-eukaryotic-translesion-synthesis-polymerases
#3
Kyle T Powers, M Todd Washington
Translesion synthesis is the process by which nonclassical DNA polymerases bypass DNA damage during DNA replication. Cells possess a variety of nonclassical polymerases, each one is specific for incorporating nucleotides opposite to one or more closely related DNA lesions, called its cognate lesions. In this chapter, we discuss a variety of approaches for probing the catalytic activities and the protein-protein interactions of nonclassical polymerases. With respect to their catalytic activities, we discuss polymerase assays, steady-state kinetics, and presteady-state kinetics...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28666590/regulation-of-dna-damage-tolerance-in-mammalian-cells-by-post-translational-modifications-of-pcna
#4
REVIEW
Rie Kanao, Chikahide Masutani
DNA damage tolerance pathways, which include translesion DNA synthesis (TLS) and template switching, are crucial for prevention of DNA replication arrest and maintenance of genomic stability. However, these pathways utilize error-prone DNA polymerases or template exchange between sister DNA strands, and consequently have the potential to induce mutations or chromosomal rearrangements. Post-translational modifications of proliferating cell nuclear antigen (PCNA) play important roles in controlling these pathways...
June 21, 2017: Mutation Research
https://www.readbyqxmd.com/read/28655184/characterization-of-a-coupled-dna-replication-and-translesion-synthesis-polymerase-supraholoenzyme-from-archaea
#5
Matthew T Cranford, Aurea M Chu, Joshua K Baguley, Robert J Bauer, Michael A Trakselis
The ability of the replisome to seamlessly coordinate both high fidelity and translesion DNA synthesis requires a means to regulate recruitment and binding of enzymes from solution. Co-occupancy of multiple DNA polymerases within the replisome has been observed primarily in bacteria and is regulated by posttranslational modifications in eukaryotes, and both cases are coordinated by the processivity clamp. Because of the heterotrimeric nature of the PCNA clamp in some archaea, there is potential to occupy and regulate specific polymerases at defined subunits...
June 26, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28642369/replisome-mediated-translesion-synthesis-by-a-cellular-replicase
#6
Philip Nevin, Carolina C Gabbai, Kenneth J Marians
Genome integrity relies on the ability of the replisome to navigate ubiquitous DNA damage during DNA replication. The Escherichia coli replisome transiently stalls at leading-strand template lesions and can either reinitiate replication downstream of the lesion or recruit specialized DNA polymerases that can bypass the lesion via translesion synthesis. Previous results had suggested that the E. coli replicase might play a role in lesion bypass, but this possibility has not been tested in reconstituted DNA replication systems...
June 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28641943/template-switching-during-replication-fork-repair-in-bacteria
#7
REVIEW
Susan T Lovett
Replication forks frequently are challenged by lesions on the DNA template, replication-impeding DNA secondary structures, tightly bound proteins or nucleotide pool imbalance. Studies in bacteria have suggested that under these circumstances the fork may leave behind single-strand DNA gaps that are subsequently filled by homologous recombination, translesion DNA synthesis or template-switching repair synthesis. This review focuses on the template-switching pathways and how the mechanisms of these processes have been deduced from biochemical and genetic studies...
June 13, 2017: DNA Repair
https://www.readbyqxmd.com/read/28607059/human-genome-wide-repair-map-of-dna-damage-caused-by-the-cigarette-smoke-carcinogen-benzo-a-pyrene
#8
Wentao Li, Jinchuan Hu, Ogun Adebali, Sheera Adar, Yanyan Yang, Yi-Ying Chiou, Aziz Sancar
Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, is the major cause of lung cancer. BaP forms covalent DNA adducts after metabolic activation and induces mutations. We have developed a method for capturing oligonucleotides carrying bulky base adducts, including UV-induced cyclobutane pyrimidine dimers (CPDs) and BaP diol epoxide-deoxyguanosine (BPDE-dG), which are removed from the genome by nucleotide excision repair. The isolated oligonucleotides are ligated to adaptors, and after damage-specific immunoprecipitation, the adaptor-ligated oligonucleotides are converted to dsDNA with an appropriate translesion DNA synthesis (TLS) polymerase, followed by PCR amplification and next-generation sequencing (NGS) to generate genome-wide repair maps...
June 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28601494/a-comparative-analysis-of-translesion-dna-synthesis-catalyzed-by-a-high-fidelity-dna-polymerase
#9
Anvesh Dasari, Tejal Deodhar, Anthony J Berdis
Translesion DNA synthesis (TLS) is the ability of DNA polymerases to incorporate nucleotides opposite and beyond damaged DNA. TLS activity is an important risk factor for the initiation and progression of genetic diseases such as cancer. In this study, we evaluate the ability of a high-fidelity DNA polymerase to perform TLS with 8-oxo-guanine (8-oxo-G), a highly pro-mutagenic DNA lesion formed by reactive oxygen species. Results of kinetic studies monitoring the incorporation of modified nucleotide analogs demonstrate that the binding affinity of the incoming dNTP is controlled by the overall hydrophobicity of the nucleobase...
July 21, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28541665/identification-of-small-molecule-translesion-synthesis-inhibitors-that-target-the-rev1-ct-rir-protein-protein-interaction
#10
Vibhavari Sail, Alessandro A Rizzo, Nimrat Chatterjee, Radha C Dash, Zuleyha Ozen, Graham C Walker, Dmitry M Korzhnev, M Kyle Hadden
Translesion synthesis (TLS) is an important mechanism through which proliferating cells tolerate DNA damage during replication. The mutagenic Rev1/Polζ-dependent branch of TLS helps cancer cells survive first-line genotoxic chemotherapy and introduces mutations that can contribute to the acquired resistance so often observed with standard anticancer regimens. As such, inhibition of Rev1/Polζ-dependent TLS has recently emerged as a strategy to enhance the efficacy of first-line chemotherapy and reduce the acquisition of chemoresistance by decreasing tumor mutation rate...
June 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28534480/molecular-basis-for-primpol-recruitment-to-replication-forks-by-rpa
#11
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
#12
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
#13
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...
July 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
#14
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
#15
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
#16
Matthew A Sanders, Brittany Haynes, Pratima Nangia-Makker, Lisa A Polin, Malathy P Shekhar
Platinum drug-induced cross-link 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...
June 23, 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
#17
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...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28474855/chromatin-regulates-genome-targeting-with-cisplatin
#18
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...
June 1, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28472716/combined-loss-of-three-dna-damage-response-pathways-renders-c-elegans-intolerant-to-light
#19
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
#20
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...
June 16, 2017: ACS Chemical Biology
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