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translesion synthesis

Mark Hedglin, Binod Pandey, Stephen J Benkovic
Translesion DNA synthesis (TLS) during S-phase uses specialized TLS DNA polymerases to replicate a DNA lesion, allowing stringent DNA synthesis to resume beyond the offending damage. Human TLS involves the conjugation of ubiquitin to PCNA clamps encircling damaged DNA and the role of this post-translational modification is under scrutiny. A widely-accepted model purports that ubiquitinated PCNA recruits TLS polymerases such as pol η to sites of DNA damage where they may also displace a blocked replicative polymerase...
October 22, 2016: ELife
Wenyan Xu, Daniel Kool, Derek K O'Flaherty, Ashley Keating, Lauralicia Sacre, Martin Egli, Anne Marietta Noronha, Christopher James Wilds, Linlin Zhao
DNA interstrand cross-links (ICLs) are cytotoxic DNA lesions derived from reactions of DNA with a number of anti-cancer reagents as well as endogenous bifunctional electrophiles. Deciphering the DNA repair mechanisms of ICLs is important for understanding the toxicity of DNA cross-linking agents and for the development of effective chemotherapies. Previous research has focused on ICLs cross-linked with the N7 and N2 atoms of guanine as well as those formed at the N6 atom of adenine; however, little is known about the mutagenicity of O6-dG-derived ICLs...
October 21, 2016: Chemical Research in Toxicology
Ashis K Basu, Paritosh Pande, Arindam Bose
With the discovery of translesion synthesis DNA polymerases, great strides have been made in the last two decades in understanding the mode of replication of various DNA lesions in prokaryotes and eukaryotes. A database search indicated that approximately 2000 articles on this topic have been published in this period. This includes research involving genetic and structural studies as well as in vitro experiments using purified DNA polymerases and accessory proteins. It is a daunting task to comprehend this exciting and rapidly emerging area of research...
October 19, 2016: Chemical Research in Toxicology
Zhoushuai Qin, Zhiqiang Bai, Ying Sun, Xiaohong Niu, Wei Xiao
In response to replication-blocking lesions, proliferating cell nuclear antigen (PCNA) can be sequentially ubiquitinated at the K164 residue leading to two modes of DNA-damage tolerance, namely translesion DNA synthesis (TLS) and error-free lesion bypass. Ectopic expression of PCNA fused with ubiquitin (Ub) lacking the two C-terminal Gly residues resembles PCNA monoubiquitination-mediated TLS. However, if the fused Ub contains C-terminal Gly residues, it is further polyubiquitinated and inhibits cell proliferation...
October 18, 2016: Cell Cycle
Amritaj Patra, Qianqian Zhang, F Peter Guengerich, Martin Egli
O6-Methyl-2(prime)-deoxyguanosine (O6-MeG) is a ubiquitous DNA lesion, formed not only by xenobiotic carcinogens but also by the endogenous methylating agent S-adenosylmethionine. It can introduce mutations during DNA replication, with different DNA polymerases displaying different ratios of correct or incorrect incoporation opposite this nucleoside. Of the "translesion" Y-family human DNA polymerases (hpols), hpol η is most efficient in incorporating equal numbers of correct and incorrect C and T bases. However, the mechanistic basis for this specific yet indescriminate activity is not known...
September 30, 2016: Journal of Biological Chemistry
Chiaki Noguchi, Grant Grothusen, Vinesh Anandarajan, Marta Martínez-Lage García, Daniel Terlecky, Krysten Corzo, Katsunori Tanaka, Hiroshi Nakagawa, Eishi Noguchi
Acetaldehyde, a primary metabolite of alcohol, forms DNA adducts and disrupts the DNA replication process, causing genomic instability, a hallmark of cancer. Indeed, chronic alcohol consumption accounts for approximately 3.6% of all cancers worldwide. However, how the adducts are prevented and repaired after acetaldehyde exposure is not well understood. In this report, we used the fission yeast Schizosaccharomyces pombe as a model organism to comprehensively understand the genetic controls of DNA damage avoidance in response to acetaldehyde...
September 29, 2016: Cell Cycle
Akira Sassa, Melike Ҫağlayan, Yesenia Rodriguez, William A Beard, Samuel H Wilson, Takehiko Nohmi, Masamitsu Honma, Manabu Yasui
Numerous ribonucleotides are incorporated into the genome during DNA replication. Oxidized ribonucleotides can also be erroneously incorporated into DNA. Embedded ribonucleotides destabilize the structure of DNA and retard DNA synthesis by DNA polymerases (pols), leading to genomic instability. Mammalian cells possess translesion DNA synthesis (TLS) pols that bypass DNA damage. The mechanism of TLS and repair of oxidized ribonucleotides remains to be elucidated. To address this, we analyzed the miscoding properties of the ribonucleotides riboguanosine (rG) and 7,8-dihydro-8-oxo-riboguanosine (8-oxo-rG) during TLS catalyzed by the human TLS pols κ and η in vitro...
September 22, 2016: Journal of Biological Chemistry
Sandra C Koch, Nina Simon, Charlotte Ebert, Thomas Carell
Nucleotide excision repair (NER) is a highly versatile and efficient DNA repair process, which is responsible for the removal of a large number of structurally diverse DNA lesions. Its extreme broad substrate specificity ranges from DNA damages formed upon exposure to ultraviolet radiation to numerous bulky DNA adducts induced by mutagenic environmental chemicals and cytotoxic drugs used in chemotherapy. Defective NER leads to serious diseases, such as xeroderma pigmentosum (XP). Eight XP complementation groups are known of which seven (XPA-XPG) are caused by mutations in genes involved in the NER process...
January 2016: Quarterly Reviews of Biophysics
Maher Awni Shahrour, Claudia M Nicolae, Simon Edvardson, Motee Ashhab, Adri M Galvan, Daniel Constantin, Bassam Abu-Libdeh, George-Lucian Moldovan, Orly Elpeleg
DNA repair mechanisms such as nucleotide excision repair (NER) and translesion synthesis (TLS) are dependent on proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory protein. Recently, homozygosity for p.Ser228Ile mutation in the PCNA gene was reported in patients with neurodegeneration and impaired NER. Using exome sequencing, we identified a homozygous deleterious mutation, c.648delAG, in the PARP10 gene, in a patient suffering from severe developmental delay. In agreement, PARP10 protein was absent from the patient cells...
October 2016: Neurogenetics
Susith Wickramaratne, Shaofei Ji, Shivam Mukherjee, Yan Su, Matthew G Pence, Lee Lior-Hoffmann, Iwen Fu, Suse Broyde, F Peter Guengerich, Mark Distefano, Orlando D Scharer, Yuk Yin Sham, Natalia Tretyakova
DNA-protein cross-links (DPCs) are bulky DNA lesions that form both endogenously and following exposure to bis-electrophiles such as common antitumor agents. The structural and biological consequences of DPCs have not been fully elucidated due to the complexity of these adducts. The most common site of DPC formation in DNA following treatment with bis-electrophiles such as nitrogen mustards and cisplatin is the N7 position of guanine, but the resulting conjugates are hydrolytically labile and thus are not suitable for structural and biological studies...
September 12, 2016: Journal of Biological Chemistry
E John Tokarsky, Varun V Gadkari, Walter J Zahurancik, Chanchal K Malik, Ashis K Basu, Zucai Suo
3-Nitrobenzanthrone (3-NBA), a byproduct of diesel exhaust, is highly present in the environment and poses a significant health risk. Exposure to 3-NBA results in formation of N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG(C8-)(N)(-ABA)), a bulky DNA lesion that is of particular importance due to its mutagenic and carcinogenic potential. If not repaired or bypassed during genomic replication, dG(C8-)(N)(-ABA) can stall replication forks, leading to senescence and cell death. Here we used pre-steady-state kinetic methods to determine which of the four human Y-family DNA polymerases (hPolη, hPolκ, hPolι, or hRev1) are able to catalyze translesion synthesis of dG(C8-)(N)(-ABA)in vitro...
October 2016: DNA Repair
T Goullet de Rugy, M Bashkurov, A Datti, R Betous, L Guitton-Sert, C Cazaux, D Durocher, J S Hoffmann
DNA polymerase theta (Polθ) is a specialized A-family DNA polymerase that functions in processes such as translesion synthesis (TLS), DNA double-strand break repair and DNA replication timing. Overexpression of POLQ, the gene encoding Polθ, is a prognostic marker for an adverse outcome in a wide range of human cancers. While increased Polθ dosage was recently suggested to promote survival of homologous recombination (HR)-deficient cancer cells, it remains unclear whether POLQ overexpression could be also beneficial to HR-proficient cancer cells...
October 15, 2016: Biology Open
Nicole L Williams, Pengcheng Wang, Yinsheng Wang
DNA alkylation represents a major type of DNA damage and is generally unavoidable due to ubiquitous exposure to various exogenous and endogenous sources of alkylating agents. Among the alkylated DNA lesions, O(2)-alkylthymidines (O(2)-alkyldT) are known to be persistent and poorly repaired in mammalian systems and have been shown to accumulate in the esophagus, lung, and liver tissue of rats treated with tobacco-specific N-nitrosamines, i.e., 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN)...
October 17, 2016: Chemical Research in Toxicology
Jae-Kwon Kim, Mina Yeom, Jin-Kyung Hong, Insil Song, Young-Sam Lee, F Peter Guengerich, Jeong-Yun Choi
DNA polymerase (pol) κ efficiently catalyzes error-free translesion DNA synthesis (TLS) opposite bulky N(2)-guanyl lesions induced by carcinogens such as polycyclic aromatic hydrocarbons. We investigated the biochemical effects of nine human nonsynonymous germline POLK variations on the TLS properties of pol κ, utilizing recombinant pol κ (residues 1-526) enzymes and DNA templates containing an N(2)-CH2(9-anthracenyl)G (N(2)-AnthG), 8-oxo-7,8-dihydroguanine (8-oxoG), O(6)-methyl(Me)G, or an abasic site. In steady-state kinetic analyses, the R246X, R298H, T473A, and R512W variants displayed 7- to 18-fold decreases in kcat/Km for dCTP insertion opposite G and N(2)-AnthG, with 2- to 3-fold decreases in DNA binding affinity, compared to that of the wild-type, and further showed 5- to 190-fold decreases in kcat/Km for next-base extension from C paired with N(2)-AnthG...
October 17, 2016: Chemical Research in Toxicology
Tetsuya Suzuki, Petr Grúz, Masamitsu Honma, Noritaka Adachi, Takehiko Nohmi
Translesion DNA synthesis (TLS) is a cellular defense mechanism against genotoxins. Defects or mutations in specialized DNA polymerases (Pols) involved in TLS are believed to result in hypersensitivity to various genotoxic stresses. Here, DNA polymerase ζ (Pol ζ)-deficient (KO: knockout) and Pol ζ catalytically dead (CD) human cells were established and their sensitivity towards cytotoxic activities of various genotoxins was examined. The CD cells were engineered by altering the DNA sequence encoding two amino acids essential for the catalytic activity of Pol ζ, i...
September 2016: Mutation Research
Tatiana Kent, Timur D Rusanov, Trung M Hoang, Willem A Velema, Andrew T Krueger, William C Copeland, Eric T Kool, Richard T Pomerantz
DNA polymerase θ (Polθ) is a unique A-family polymerase that is essential for alternative end-joining (alt-EJ) of double-strand breaks (DSBs) and performs translesion synthesis. Because Polθ is highly expressed in cancer cells, confers resistance to ionizing radiation and chemotherapy agents, and promotes the survival of homologous recombination (HR) deficient cells, it represents a promising new cancer drug target. As a result, identifying substrates that are selective for this enzyme is a priority. Here, we demonstrate that Polθ efficiently and selectively incorporates into DNA large benzo-expanded nucleotide analogs (dxAMP, dxGMP, dxTMP, dxAMP) which exhibit canonical base-pairing and enhanced base stacking...
September 2, 2016: Nucleic Acids Research
Elisa Mentegari, Miroslava Kissova, Laura Bavagnoli, Giovanni Maga, Emmanuele Crespan
DNA is constantly exposed to both endogenous and exogenous damages. More than 10,000 DNA modifications are induced every day in each cell's genome. Maintenance of the integrity of the genome is accomplished by several DNA repair systems. The core enzymes for these pathways are the DNA polymerases. Out of 17 DNA polymerases present in a mammalian cell, at least 13 are specifically devoted to DNA repair and are often acting in different pathways. DNA polymerases β and λ are involved in base excision repair of modified DNA bases and translesion synthesis past DNA lesions...
2016: Genes
J Sidney Ang, Supipi Duffy, Romulo Segovia, Peter C Stirling, Philip Hieter
Mutations that cause genome instability are considered important predisposing events that contribute to initiation and progression of cancer. Genome instability arises either due to defects in genes that cause an increased mutation rate (mutator phenotype) or defects in genes that cause chromosome instability (CIN). To extend the catalogue of genome instability genes, we systematically explored the effects of gene over-expression on mutation rate, using a forward-mutation screen in budding yeast. We screened ~5100 plasmids, each over-expressing a unique single gene and characterized the five strongest mutators, MPH1, RRM3, UBP12, PIF1 and DNA2 We show that for MPH1, the yeast homolog of Fanconi Anemia complementation group M (FANCM), the over-expression mutator phenotype is distinct from that of mph1Δ...
August 31, 2016: Genetics
D K O'Flaherty, A Patra, Y Su, F P Guengerich, M Egli, C J Wilds
DNA lesions that elude repair may undergo translesion synthesis catalyzed by Y-family DNA polymerases. O (4)-Alkylthymidines, persistent adducts that can result from carcinogenic agents, may be encountered by DNA polymerases. The influence of lesion orientation around the C4-O (4) bond on processing by human DNA polymerase η (hPol η) was studied for oligonucleotides containing O (4)-methylthymidine, O (4)-ethylthymidine, and analogs restricting the O (4)-methylene group in an anti-orientation. Primer extension assays revealed that the O (4)-alkyl orientation influences hPol η bypass...
August 1, 2016: Chemical Science
Jeong-Yun Choi, Amritaj Patra, Mina Yeom, Young-Sam Lee, Qianqian Zhang, Martin Egli, F Peter Guengerich
DNA polymerase (pol) ι is a Y-family polymerase involved in translesion synthesis, exhibiting higher catalytic activity with Mn(2+) than Mg(2+) The human germline R96G variant impairs both Mn(2+)-dependent and Mg(2+)-dependent activities of pol ι, whereas the Δ1-25 variant selectively enhances its Mg(2+)-dependent activity. We analyzed pre-steady-state kinetic and structural effects of these two metal ions and genetic variations on pol ι using pol ι core (residues 1-445) proteins. The presence of Mn(2+) (0...
September 30, 2016: Journal of Biological Chemistry
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