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translesion synthesis

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https://www.readbyqxmd.com/read/27907204/homologous-recombination-and-translesion-dna-synthesis-play-critical-roles-on-tolerating-dna-damage-caused-by-trace-levels-of-hexavalent-chromium
#1
Xu Tian, Keyur Patel, John R Ridpath, Youjun Chen, Yi-Hui Zhou, Dayna Neo, Jean Clement, Minoru Takata, Shunichi Takeda, Julian Sale, Fred A Wright, James A Swenberg, Jun Nakamura
Contamination of potentially carcinogenic hexavalent chromium (Cr(VI)) in the drinking water is a major public health concern worldwide. However, little information is available regarding the biological effects of a nanomoler amount of Cr(VI). Here, we investigated the genotoxic effects of Cr(VI) at nanomoler levels and their repair pathways. We found that DNA damage response analyzed based on differential toxicity of isogenic cells deficient in various DNA repair proteins is observed after a three-day incubation with K2CrO4 in REV1-deficient DT40 cells at 19...
2016: PloS One
https://www.readbyqxmd.com/read/27894771/radiation-induced-dna-protein-cross-links-mechanisms-and-biological-significance
#2
Toshiaki Nakano, Xu Xu, Amir M H Salem, Mahmoud I Shoulkamy, Hiroshi Ide
Ionizing radiation produces various DNA lesions such as base damage, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and DNA-protein cross-links (DPCs). Of these, the biological significance of DPCs remains elusive. In this article, we focus on radiation-induced DPCs and review the current understanding of their induction, properties, repair, and biological consequences. When cells are irradiated, the formation of base damage, SSBs, and DSBs are promoted in the presence of oxygen. Conversely, that of DPCs is promoted in the absence of oxygen, suggesting their importance in hypoxic cells, such as those present in tumors...
November 25, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27893960/eukaryotic-dna-polymerases-in-homologous-recombination
#3
Mitch McVey, Varandt Y Khodaverdian, Damon Meyer, Paula Gonçalves Cerqueira, Wolf-Dietrich Heyer
Homologous recombination (HR) is a central process to ensure genomic stability in somatic cells and during meiosis. HR-associated DNA synthesis determines in large part the fidelity of the process. A number of recent studies have demonstrated that DNA synthesis during HR is conservative, less processive, and more mutagenic than replicative DNA synthesis. In this review, we describe mechanistic features of DNA synthesis during different types of HR-mediated DNA repair, including synthesis-dependent strand annealing, break-induced replication, and meiotic recombination...
November 23, 2016: Annual Review of Genetics
https://www.readbyqxmd.com/read/27862447/minor-groove-3-deaza-adenosine-analogs-synthesis-and-bypass-in-translesion-dna-synthesis
#4
Stefano Malvezzi, Todor Angelov, Shana Jocette Sturla
Anticancer drugs that alkylate DNA in the minor groove may give rise to 3-alkyl-adenosine adducts that interfere with replication, inducing apoptosis in rapidly dividing cancer cells. However, translesion DNA synthesis (TLS) by polymerase enzymes (Pols) with the capacity to bypass DNA adducts may contribute to damage tolerance and drug resistance. 3-Alkyl-adenosine adducts are unstable and depurinate, a barrier to addressing chemical and enzymatic aspects of how they impact the progress of DNA Pols. To characterize structure-based relationships of 3-adenine alkylation relevant to cancer drugs on duplex stability and DNA Pol-catalyzed DNA synthesis, we synthesized stable 3-deaza-3-alkyl-adenosine adducts, including 3-deaza-3-phenethyl-adenosine and 3-deaza-3-methoxynaphthylethyl-adenosine, and incorporated them into oligonucleotides...
November 10, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27829668/next-generation-sequencing-of-benzo-a-pyrene-induced-lacz-mutants-identifies-a-germ-cell-specific-mutation-spectrum
#5
Jason M O'Brien, Marc A Beal, Carole L Yauk, Francesco Marchetti
De novo mutations are implicated in a variety of genetic diseases and arise primarily in the male germline. We investigated whether male germ cells have unique mechanisms for spontaneous or chemically-induced mutation relative to somatic cells using the MutaMouse model. We recovered lacZ transgenes from sperm 42 days after a 28-day exposure to benzo(a)pyrene (BaP, 100 mg/kg/day) to assess mutations arising in dividing spermatogonia. BaP caused a 3.4-fold increase in lacZ mutant frequency over controls which increased to 4...
November 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27829156/proteomic-profiling-reveals-a-specific-role-for-translesion-dna-polymerase-%C3%AE-in-the-alternative-lengthening-of-telomeres
#6
Laura Garcia-Exposito, Elodie Bournique, Valérie Bergoglio, Arindam Bose, Jonathan Barroso-Gonzalez, Sufang Zhang, Justin L Roncaioli, Marietta Lee, Callen T Wallace, Simon C Watkins, Patricia L Opresko, Jean-Sébastien Hoffmann, Roderick J O'Sullivan
Cancer cells rely on the activation of telomerase or the alternative lengthening of telomeres (ALT) pathways for telomere maintenance and survival. ALT involves homologous recombination (HR)-dependent exchange and/or HR-associated synthesis of telomeric DNA. Utilizing proximity-dependent biotinylation (BioID), we sought to determine the proteome of telomeres in cancer cells that employ these distinct telomere elongation mechanisms. Our analysis reveals that multiple DNA repair networks converge at ALT telomeres...
November 8, 2016: Cell Reports
https://www.readbyqxmd.com/read/27819052/structure-and-mechanism-of-human-primpol-a-dna-polymerase-with-primase-activity
#7
Olga Rechkoblit, Yogesh K Gupta, Radhika Malik, Kanagalaghatta R Rajashankar, Robert E Johnson, Louise Prakash, Satya Prakash, Aneel K Aggarwal
PrimPol is a novel human enzyme that contains both DNA primase and DNA polymerase activities. We present the first structure of human PrimPol in ternary complex with a DNA template-primer and an incoming deoxynucleoside triphosphate (dNTP). The ability of PrimPol to function as a DNA primase stems from a simple but remarkable feature-almost complete lack of contacts to the DNA primer strand. This, in turn, allows two dNTPs to bind initiation and elongation sites on the enzyme for the formation of the first dinucleotide...
October 2016: Science Advances
https://www.readbyqxmd.com/read/27814655/mitochondrial-dna-repair-and-damage-tolerance
#8
Alexis Stein, Elaine A Sia
The accurate maintenance of mitochondrial DNA (mtDNA) is required in order for eukaryotic cells to assemble a functional electron transport chain. This independently-maintained genome relies on nuclear-encoded proteins that are imported into the mitochondria to carry out replication and repair processes. Decades of research has made clear that mitochondria employ robust and varied mtDNA repair and damage tolerance mechanisms in order to ensure the proper maintenance of the mitochondrial genome. This review focuses on our current understanding of mtDNA repair and damage tolerance pathways including base excision repair, mismatch repair, homologous recombination, non-homologous end joining, translesion synthesis and mtDNA degradation in both yeast and mammalian systems...
January 1, 2017: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/27770570/characterization-of-human-translesion-dna-synthesis-across-a-uv-induced-dna-lesion
#9
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
https://www.readbyqxmd.com/read/27768841/o6-2-deoxyguanosine-butylene-o6-2-deoxyguanosine-dna-interstrand-cross-links-are-replication-blocking-and-mutagenic-dna-lesions
#10
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
https://www.readbyqxmd.com/read/27760288/translesion-synthesis-of-2-deoxyguanosine-lesions-by-eukaryotic-dna-polymerases
#11
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
https://www.readbyqxmd.com/read/27753536/pcna-ub-polyubiquitination-inhibits-cell-proliferation-and-induces-cell-cycle-checkpoints
#12
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
https://www.readbyqxmd.com/read/27694439/mechanisms-of-insertion-of-dctp-and-dttp-opposite-the-dna-lesion-o6-methyl-2-deoxyguanosine-by-human-dna-polymerase-%C3%AE
#13
Amitraj Patra, Qianqian Zhang, F Peter Guengerich, Martin Egli
O(6)-Methyl-2'-deoxyguanosine (O(6)-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 incorporation 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 indiscriminate activity is not known...
November 11, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27687866/genetic-controls-of-dna-damage-avoidance-in-response-to-acetaldehyde-in-fission-yeast
#14
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
https://www.readbyqxmd.com/read/27660390/impact-of-ribonucleotide-backbone-on-translesion-synthesis-and-repair-of-7-8-dihydro-8-oxoguanine
#15
Akira Sassa, Melike Çağlayan, 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 The primer extension reaction catalyzed by human replicative pol α was strongly blocked by 8-oxo-rG...
November 11, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27660069/molecular-mechanisms-of-xeroderma-pigmentosum-xp-proteins
#16
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
https://www.readbyqxmd.com/read/27624574/parp10-deficiency-manifests-by-severe-developmental-delay-and-dna-repair-defect
#17
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
https://www.readbyqxmd.com/read/27621316/bypass-of-dna-protein-cross-links-conjugated-to-the-7-deazaguanine-position-of-dna-by-translesion-synthesis-polymerases
#18
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 Schärer, 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...
November 4, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27612622/pre-steady-state-kinetic-investigation-of-bypass-of-a-bulky-guanine-lesion-by-human-y-family-dna-polymerases
#19
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
https://www.readbyqxmd.com/read/27612511/excess-pol%C3%AE-functions-in-response-to-replicative-stress-in-homologous-recombination-proficient-cancer-cells
#20
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
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