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translesion synthesis

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...
February 26, 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...
March 5, 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...
January 29, 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 IC 50 value of 8 μM and exhibited 5-10-fold specificity for hpol η over replicative pols...
January 30, 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 an ubiquitous environmental pollutant. The reaction of acrolein with the N2 of guanine in DNA leads to the formation of γ-hydroxy-1-N2-propano-2' deoxyguanosine (γ-HOPdG) which can exist in DNA in a ring-closed or a ring-opened form. Here we identify the translesion synthesis (TLS) DNA polymerases (Pols) which 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...
January 12, 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...
January 3, 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 27, 2017: PLoS Genetics
Jung-Suk Choi, Casey S Kim, Anthony Berdis
Temozolomide is a DNA alkylating agent used to treat brain tumors but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by co-administration of an artificial nucleoside (5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate 5-NITP in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA...
December 19, 2017: Cancer Research
Jun-Ichi Akagi, Masayuki Yokoi, Young-Man Cho, Takeshi Toyoda, Haruo Ohmori, Fumio Hanaoka, Kumiko Ogawa
Genotoxic agents cause modifications of genomic DNA, such as alkylation, oxidation, bulky adduct formation, and strand breaks, which potentially induce mutations and changes to the structure or number of genes. Majority of point mutations are generated during error-prone bypass of modified nucleotides (translesion DNA synthesis, TLS); however, when TLS fails, replication forks stalled at lesions eventually result in more lethal effects, formation of double-stranded breaks (DSBs). Here we compared sensitivities to various compounds among mouse embryonic fibroblasts derived from wild-type and knock-out mice lacking one of the three Y-family TLS DNA polymerases (Polη, Polι, and Polκ) or all of them (TKO)...
November 26, 2017: DNA Repair
Daniel J Laverty, Marc M Greenberg
Unrepaired DNA lesions block replication and threaten genomic stability. Several specialized translesion polymerases, including polymerase θ (Pol θ), contribute to replicative bypass of these lesions. The role of Pol θ in double-strand break repair is well-understood, but its contribution to translesion synthesis is much less so. We describe the action of Pol θ on templates containing thymidine glycol (Tg), a major cytotoxic, oxidative DNA lesion that blocks DNA replication. Unrepaired Tg lesions are bypassed in human cells by specialized translesion polymerases by one of two distinct pathways: high-fidelity bypass by the combined action of Pol κ and Pol ζ or weakly mutagenic bypass by Pol θ...
December 26, 2017: Biochemistry
O Novakova, N P Farrell, V Brabec
Polynuclear platinum complexes represent a unique structural class of DNA-binding agents of biological significance. They contain at least two platinum coordinating units bridged by a linker, which means that the formation of double-base lesions (cross-links) in DNA is possible. Here, we show that the lead compound, bifunctional [{trans-PtCl(NH3)2}2μ-trans-Pt(NH3)2{H2N(CH2)6NH2}2]4+ (Triplatin or BBR3464), forms in DNA specific double-base lesions which affect the biophysical and biochemical properties of DNA in a way fundamentally different compared to the analogous double-base lesions formed by two adducts of monofunctional chlorodiethylenetriamineplatinum(ii) chloride (dienPt)...
December 15, 2017: Metallomics: Integrated Biometal Science
Pramodha S Liyanage, Alice R Walker, Alfonso Brenlla, G Andrés Cisneros, Louis J Romano, David Rueda
Translesion DNA synthesis is an essential process that helps resume DNA replication at forks stalled near bulky adducts on the DNA. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon (PAH) that can be metabolically activated to benzo[a]pyrene diol epoxide (BPDE), which then can react with DNA to form carcinogenic DNA adducts. Here, we have used single-molecule florescence resonance energy transfer (smFRET) experiments, classical molecular dynamics simulations, and nucleotide incorporation assays to investigate the mechanism by which the model Y-family polymerase, Dpo4, bypasses a (+)-cis-B[a]P-N 2-dG adduct in DNA...
December 12, 2017: Scientific Reports
Gengjing Zhao, Emma S Gleave, Meindert Hugo Lamers
High fidelity replicative DNA polymerases are unable to synthesize past DNA adducts that result from diverse chemicals, reactive oxygen species or UV light. To bypass these replication blocks, cells utilize specialized translesion DNA polymerases that are intrinsically error prone and associated with mutagenesis, drug resistance, and cancer. How untimely access of translesion polymerases to DNA is prevented is poorly understood. Here we use co-localization single-molecule spectroscopy (CoSMoS) to follow the exchange of the E...
December 6, 2017: ELife
Xiaolu Ma, Hongmei Liu, Jing Li, Yihao Wang, Yue-He Ding, Hongyan Shen, Yeran Yang, Chenyi Sun, Min Huang, Yingfeng Tu, Yang Liu, Yongliang Zhao, Meng-Qiu Dong, Ping Xu, Tie-Shan Tang, Caixia Guo
DNA polymerase η (Polη) facilitates translesion DNA synthesis (TLS) across ultraviolet (UV) irradiation- and cisplatin-induced DNA lesions implicated in skin carcinogenesis and chemoresistant phenotype formation, respectively. However, whether post-translational modifications of Polη are involved in these processes remains largely unknown. Here, we reported that human Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase upon DNA damage. Abrogation of this modification results in a reduced level of CRL4CDT2 -dependent Polη polyubiquitination at lysine 462, a delayed p97-dependent removal of Polη from replication forks, and significantly enhanced UV-induced mutagenesis even though Polη focus formation and its efficacy to bypass across cyclobutane pyrimidine dimers after UV irradiation are not affected...
December 5, 2017: Nature Communications
Ewa Szwajczak, Iwona J Fijalkowska, Catherine Suski
Precisely controlled mechanisms have been evolved to rescue impeded DNA replication resulting from encountered obstacles and involve a set of low-fidelity translesion synthesis (TLS) DNA polymerases. Studies in recent years have brought new insights into those TLS polymerases, especially concerning the structure and subunit composition of DNA polymerase zeta (Pol ζ). Pol ζ is predominantly involved in induced mutagenesis as well as the bypass of noncanonical DNA structures, and it is proficient in extending from terminal mismatched nucleotides incorporated by major replicative DNA polymerases...
November 30, 2017: Current Genetics
Zhoushuai Qin, Wandong Jiang, Guifen Wang, Ying Sun, Wei Xiao
Ubiquitination of proliferating cell nuclear antigen (PCNA) plays an important role in DNA damage response. Ectopic expression of PCNA fused at either terminus with ubiquitin (Ub) lacking two C-terminal glycine residues induces translesion DNA synthesis which resembles synthesis mediated by PCNA monoubiquitination. PCNA fused with Ub containing the C-terminal Gly residues at the C-terminus can be further polyubiquitinated in a Gly-dependent manner, which inhibits cell proliferation and induces ATR-dependent replication checkpoint...
January 2018: Apoptosis: An International Journal on Programmed Cell Death
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