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translesion synthesis

Gaofeng Cui, Maria Victoria Botuyan, Georges Mer
REV1 is an evolutionarily conserved Translesion synthesis (TLS) DNA polymerase and an assembly factor key for the recruitment of other TLS polymerases to DNA damage sites. REV1-mediated recognition of ubiquitin in the proliferative cell nuclear antigen (PCNA) is thought to be the trigger for TLS activation. Here we report the solution nuclear magnetic resonance (NMR) structure of a 108-residue fragment of human REV1 encompassing the two putative ubiquitin-binding motifs UBM1 and UBM2 in complex with ubiquitin...
May 17, 2018: Journal of Molecular Biology
Kiminori Kurashima, Takayuki Sekimoto, Tsukasa Oda, Tsuyoshi Kawabata, Fumio Hanaoka, Takayuki Yamashita
Growth of precancerous and cancer cells relies on their tolerance of oncogene-induced replication stress (RS). Translesion synthesis (TLS) plays an essential role in cellular tolerance of various types of RS and bypasses replication barriers by employing specialized polymerases. However, limited information is available about the role of TLS polymerases in oncogene-induced RS. Here, we report that Polη, a Y-family TLS polymerase, promotes cellular tolerance of Myc-induced RS. Polη was recruited to Myc-induced RS sites, and Polη depletion enhanced the Myc-induced slowing and stalling of replication forks and the subsequent generation of double-strand breaks (DSBs)...
May 18, 2018: Journal of Cell Science
Vikash Jha, Hong Ling
Cisplatin (cis-diamminedichloroplatinum) is a common chemotherapeutic drug that reacts with the N7 atoms of adjacent guanines in DNA to form the Pt-1,2-d(GpG) intrastrand cross-link (Pt-GG), a major product to block DNA replication. Translesion DNA synthesis has been implicated in chemoresistance during cisplatin treatment of cancer due to Pt-GG lesion bypass. Gene knockdown studies in human cells have indicated a role for polκ during translesion synthesis of the Pt-GG lesion. However, the bypass activity of polκ with cisplatin lesions has not been well characterized...
April 28, 2018: Journal of Molecular Biology
Fengyu Liu, Yulong Yang, Yajing Zhou
Precise duplication of the human genome is constantly threatened by a variety of genotoxic insults. During S-phase, those damaged template bases could be overcome by DNA damage tolerance (DDT) pathways that bypass such obstacles instead of repairing them, allowing replicative machinery to resume beyond the offending lesions. Two distinct strategies of DDT, template switching and translesion DNA synthesis (TLS), are employed in eukaryotes. In the former process, the newly synthesized sister chromatid is utilized as an undamaged template to restart recombination-dependent DNA synthesis in an error-free manner...
April 30, 2018: Current Protein & Peptide Science
Petr Grúz, Masatomi Shimizu, Masami Yamada, Kei-Ichi Sugiyama, Masamitsu Honma
DNA polymerases play a key role in mutagenesis by performing translesion DNA synthesis (TLS). The Y-family of DNA polymerases comprises several evolutionarily conserved families, specializing in TLS of different DNA adducts. Exocyclic etheno and propano DNA adducts are among the most common endogenous DNA lesions induced by lipid peroxidation reactions triggered by oxidative stress. We have investigated the participation of two enterobacterial representatives of the PolIV and PolV branches of Y-family DNA polymerases in mutagenesis by two model lipid peroxidation derived genotoxins, glyoxal and crotonaldehyde...
May 2018: Mutation Research
Sarah S Henrikus, Antoine M van Oijen, Andrew Robinson
In many bacterial species, DNA damage triggers the SOS response; a pathway that regulates the production of DNA repair and damage tolerance proteins, including error-prone DNA polymerases. These specialised polymerases are capable of bypassing lesions in the template DNA, a process known as translesion synthesis (TLS). Specificity for lesion types varies considerably between the different types of TLS polymerases. TLS polymerases are mainly described as working in the context of replisomes that are stalled at lesions or in lesion-containing gaps left behind the replisome...
April 26, 2018: Current Genetics
Jun Wu, Pengcheng Wang, Lin Li, Changjun You, Yinsheng Wang
Endogenous metabolism, environmental exposure, and cancer chemotherapy can lead to alkylation of DNA. It has been well documented that, among the different DNA alkylation products, minor-groove O 2 -alkylthymidine ( O 2 -alkyldT) lesions are inefficiently repaired. In the present study, we examined how seven O 2 -alkyldT lesions, with the alkyl group being a Me, Et, n Pr, i Pr, n Bu, i Bu or s Bu, are recognized by the DNA replication machinery in human cells. We found that the replication bypass efficiencies of these lesions decrease with increasing length of the alkyl chain, and that these lesions induce substantial frequencies of T→A and T→G mutations...
April 23, 2018: Journal of Biological Chemistry
Antoine Simoneau, Étienne Ricard, Hugo Wurtele
The evolutionarily-conserved sirtuin family of histone deacetylases regulates a multitude of DNA-associated processes. A recent genome-wide screen conducted in the yeast Saccharomyces cerevisiae identified Yku70/80, which regulate nonhomologous end-joining (NHEJ) and telomere structure, as being essential for cell proliferation in the presence of the pan-sirtuin inhibitor nicotinamide (NAM). Here, we show that sirtuin-dependent deacetylation of both histone H3 lysine 56 and H4 lysine 16 promotes growth of yku70Δ and yku80Δ cells, and that the NAM sensitivity of these mutants is not caused by defects in double-strand break repair by NHEJ, but rather by their inability to maintain normal telomere length...
April 16, 2018: PLoS Genetics
Min Huang, Bo Zhou, Juanjuan Gong, Lingyu Xing, Xiaolu Ma, Fengli Wang, Wei Wu, Hongyan Shen, Chenyi Sun, Xuefei Zhu, Yeran Yang, Yazhou Sun, Yang Liu, Tie-Shan Tang, Caixia Guo
Translesion DNA synthesis (TLS) is one mode of DNA damage tolerance that uses specialized DNA polymerases to replicate damaged DNA. DNA polymerase η (Polη) is well known to facilitate TLS across ultraviolet (UV) irradiation and mutations in POLH are implicated in skin carcinogenesis. However, the basis for recruitment of Polη to stalled replication forks is not completely understood. In this study, we used an affinity purification approach to isolate a Polη-containing complex and have identified SART3, a pre-mRNA splicing factor, as a critical regulator to modulate the recruitment of Polη and its partner RAD18 after UV exposure...
March 24, 2018: Nucleic Acids Research
Élodie Chrabaszcz, Luisa Laureti, Vincent Pagès
The genome of all organisms is constantly threatened by numerous agents that cause DNA damage. When the replication fork encounters an unrepaired DNA lesion, two DNA damage tolerance pathways are possible: error-prone translesion synthesis (TLS) that requires specialized DNA polymerases, and error-free damage avoidance that relies on homologous recombination (HR). The balance between these two mechanisms is essential since it defines the level of mutagenesis during lesion bypass, allowing genetic variability and adaptation to the environment, but also introduces the risk of generating genome instability...
May 4, 2018: Nucleic Acids Research
Jiabin Wu, Pengcheng Wang, Yinsheng Wang
Exposure to many endogenous and exogenous agents can give rise to DNA alkylation, which constitutes a major type of DNA damage. Among the DNA alkylation products, alkyl phosphotriesters have relatively high frequencies of occurrence and are resistant to repair in mammalian tissues. However, little is known about how these lesions affect the efficiency and fidelity of DNA replication in cells or how the replicative bypass of these lesions is modulated by translesion synthesis DNA polymerases. In this study, we synthesized oligodeoxyribonucleotides containing four pairs (Sp and Rp) of alkyl phosphotriester lesions at a defined site, and examined how these lesions are recognized by DNA replication machinery in Escherichia coli cells...
May 4, 2018: Nucleic Acids Research
Wei Yang, Yang Gao
The number of DNA polymerases identified in each organism has mushroomed in last two decades. Most newly found DNA polymerases specialize in translesion synthesis and DNA repair instead of replication. Although intrinsic error rates are higher for translesion and repair polymerases than for replicative polymerases, the specialized polymerases increase genome stability and reduce tumorigenesis. Reflecting the numerous types ofDNAlesions and variations of broken DNA ends, translesion and repair polymerases differ in structure, mechanism, and function...
March 1, 2018: Annual Review of Biochemistry
Qifu Fan, Xin Xu, Xi Zhao, Qian Wang, Wei Xiao, Ying Guo, Yu V Fu
DNA repair is essential to maintain genome integrity. In addition to various DNA repair pathways dealing with specific types of DNA lesions, DNA damage tolerance (DDT) promotes the bypass of DNA replication blocks encountered by the replication fork to prevent cell death. Budding yeast Rad5 plays an essential role in the DDT pathway and its structure indicates that Rad5 recognizes damaged DNA or stalled replication forks, suggesting that Rad5 plays an important role in the DDT pathway choice. It has been reported that Rad5 forms subnuclear foci in the presence of methyl methanesulfonate (MMS) during the S phase...
February 2, 2018: Current Genetics
Kyle T Powers, Adrian H Elcock, M Todd Washington
Eukaryotic DNA polymerase η catalyzes translesion synthesis of thymine dimers and 8-oxoguanines. It is comprised of a polymerase domain and a C-terminal region, both of which are required for its biological function. The C-terminal region mediates interactions with proliferating cell nuclear antigen (PCNA) and other translesion synthesis proteins such as Rev1. This region contains a ubiquitin-binding/zinc-binding (UBZ) motif and a PCNA-interacting protein (PIP) motif. Currently little structural information is available for this region of polymerase η...
February 28, 2018: Nucleic Acids Research
Maroof K Zafar, Leena Maddukuri, Amit Ketkar, Narsimha R Penthala, Megan R Reed, Sarah Eddy, Peter A Crooks, Robert L Eoff
Translesion DNA synthesis (TLS) performed by human DNA polymerase eta (hpol η) allows tolerance of damage from cis-diamminedichloroplatinum(II) (CDDP or cisplatin). We have developed hpol η inhibitors derived from N-aryl-substituted indole barbituric acid (IBA), indole thiobarbituric acid (ITBA), and indole quinuclidine scaffolds and identified 5-((5-chloro-1-(naphthalen-2-ylmethyl)-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (PNR-7-02), an ITBA derivative that inhibited hpol η activity with an IC50 value of 8 μM and exhibited 5-10-fold specificity for hpol η over replicative pols...
February 20, 2018: Biochemistry
Jung-Hoon Yoon, Richard P Hodge, Linda C Hackfeld, Jeseong Park, Jayati Roy Choudhury, Satya Prakash, Louise Prakash
Acrolein, an α,β-unsaturated aldehyde, is generated in vivo as the end product of lipid peroxidation and from metabolic oxidation of polyamines, and it is a ubiquitous environmental pollutant. The reaction of acrolein with the N2 of guanine in DNA leads to the formation of γ-hydroxy-1- N 2 -propano-2' deoxyguanosine (γ-HOPdG), which can exist in DNA in a ring-closed or a ring-opened form. Here, we identified the translesion synthesis (TLS) DNA polymerases (Pols) that conduct replication through the permanently ring-opened reduced form of γ-HOPdG ((r) γ-HOPdG) and show that replication through this adduct is mediated via Rev1/Polη-, Polι/Polκ-, and Polθ-dependent pathways, respectively...
February 23, 2018: Journal of Biological Chemistry
Shitao Zou, Jianlong Yang, Jiaming Guo, Ye Su, Chao He, Jinchang Wu, Lan Yu, Wei-Qun Ding, Jundong Zhou
As a key regulator of DNA translesion synthesis (TLS) pathway, RAD18 is error-prone and contributes to the accumulation of DNA mutations. We have recently shown that RAD18 is overexpressed in human esophageal squamous cell cancer (ESCC) and acts to promote ESCC progression. The current study aims to understand the molecular mechanism by which RAD18 enhances the invasiveness and metastasis of ESCC cells. We found that RAD18 expression is markedly higher in high T stage ESCCs compared to low T stage groups. Kaplan-Meier analysis showed an inverse correlation between RAD18 expression and patient prognosis...
March 28, 2018: Cancer Letters
Vinit Shanbhag, Shrikesh Sachdev, Jacqueline A Flores, Mukund J Modak, Kamalendra Singh
DNA polymerases are essential for genome replication, DNA repair and translesion DNA synthesis (TLS). Broadly, these enzymes belong to two groups: replicative and non-replicative DNA polymerases. A considerable body of data suggests that both groups of DNA polymerases are associated with cancer. Many mutations in cancer cells are either the result of error-prone DNA synthesis by non-replicative polymerases, or the inability of replicative DNA polymerases to proofread mismatched nucleotides due to mutations in 3'-5' exonuclease activity...
January 2, 2018: Biology
Kenneth J Marians
Accurate transmission of the genetic information requires complete duplication of the chromosomal DNA each cell division cycle. However, the idea that replication forks would form at origins of DNA replication and proceed without impairment to copy the chromosomes has proven naive. It is now clear that replication forks stall frequently as a result of encounters between the replication machinery and template damage, slow-moving or paused transcription complexes, unrelieved positive superhelical tension, covalent protein-DNA complexes, and as a result of cellular stress responses...
January 3, 2018: Annual Review of Biochemistry
Carine Tellier-Lebegue, Eléa Dizet, Emilie Ma, Xavier Veaute, Eric Coïc, Jean-Baptiste Charbonnier, Laurent Maloisel
Replicative DNA polymerases cannot insert efficiently nucleotides at sites of base lesions. This function is taken over by specialized translesion DNA synthesis (TLS) polymerases to allow DNA replication completion in the presence of DNA damage. In eukaryotes, Rad6- and Rad18-mediated PCNA ubiquitination at lysine 164 promotes recruitment of TLS polymerases, allowing cells to efficiently cope with DNA damage. However, several studies showed that TLS polymerases can be recruited also in the absence of PCNA ubiquitination...
December 2017: PLoS Genetics
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