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translesion synthesis

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https://www.readbyqxmd.com/read/29330301/genetic-control-of-predominantly-error-free-replication-through-an-acrolein-derived-minor-groove-dna-adduct
#1
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
https://www.readbyqxmd.com/read/29306013/rad18-promotes-the-migration-and-invasion-of-esophageal-squamous-cell-cancer-via-the-jnk-mmps-pathway
#2
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
https://www.readbyqxmd.com/read/29301327/family-a-and-b-dna-polymerases-in-cancer-opportunities-for-therapeutic-interventions
#3
REVIEW
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
https://www.readbyqxmd.com/read/29298091/lesion-bypass-and-the-reactivation-of-stalled-replication-forks
#4
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
https://www.readbyqxmd.com/read/29281621/the-translesion-dna-polymerases-pol-%C3%AE-and-rev1-are-activated-independently-of-pcna-ubiquitination-upon-uv-radiation-in-mutants-of-dna-polymerase-%C3%AE
#5
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
https://www.readbyqxmd.com/read/29259011/inhibition-of-translesion-dna-synthesis-as-a-novel-therapeutic-strategy-to-treat-brain-cancer
#6
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
https://www.readbyqxmd.com/read/29247828/hypersensitivity-of-mouse-embryonic-fibroblast-cells-defective-for-dna-polymerases-%C3%AE-%C3%AE-and-%C3%AE%C2%BA-to-various-genotoxic-compounds-its-potential-for-application-in-chemical-genotoxic-screening
#7
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
https://www.readbyqxmd.com/read/29243925/in-vitro-bypass-of-thymidine-glycol-by-dna-polymerase-%C3%AE-forms-sequence-dependent-frameshift-mutations
#8
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
https://www.readbyqxmd.com/read/29242879/translesion-dna-synthesis-across-double-base-lesions-derived-from-cross-links-of-an-antitumor-trinuclear-platinum-compound-primer-extension-conformational-and-thermodynamic-studies
#9
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
https://www.readbyqxmd.com/read/29234107/bulky-lesion-bypass-requires-dpo4-binding-in-distinct-conformations
#10
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
https://www.readbyqxmd.com/read/29210356/single-molecule-studies-contrast-ordered-dna-replication-with-stochastics-translesion-synthesis
#11
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
https://www.readbyqxmd.com/read/29208956/pol%C3%AE-o-glcnacylation-governs-genome-integrity-during-translesion-dna-synthesis
#12
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
https://www.readbyqxmd.com/read/29189894/the-importance-of-an-interaction-network-for-proper-dna-polymerase-%C3%AE-heterotetramer-activity
#13
REVIEW
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
https://www.readbyqxmd.com/read/29185083/linear-ubiquitin-chain-induces-apoptosis-and-inhibits-tumor-growth
#14
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...
November 28, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/29149833/g4-interacting-dna-helicases-and-polymerases-potential-therapeutic-targets
#15
Katrina Estep, Thomas J Butler, Jun Ding, Robert M Brosh
Guanine-rich DNA can fold into highly stable non-canonical four-stranded DNA structures called G-quadruplexes. These structures present obstacles for the DNA replication machinery, and it has been hypothesized that both eukaryotic DNA helicases and polymerases have evolved to resolve G4 DNA in vivo. Since the discovery of G-quadruplex DNA in the early 1960's, a number of studies have emerged reporting G-quadruplex DNA unfolding by helicase enzymes and DNA synthesis past G4 by specialized translesion polymerase enzymes...
November 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29104772/non-bulky-lesions-in-human-dna-the-ways-of-formation-repair-and-replication
#16
A V Ignatov, K A Bondarenko, A V Makarova
DNA damage is a major cause of replication interruption, mutations, and cell death. DNA damage is removed by several types of repair processes. The involvement of specialized DNA polymerases in replication provides an important mechanism that helps tolerate persistent DNA damage. Specialized DNA polymerases incorporate nucleotides opposite lesions with high efficiency but demonstrate low accuracy of DNA synthesis. In this review, we summarize the types and mechanisms of formation and repair of non-bulky DNA lesions, and we provide an overview of the role of specialized DNA polymerases in translesion DNA synthesis...
July 2017: Acta Naturae
https://www.readbyqxmd.com/read/29076178/limited-ability-of-dna-polymerase-kappa-to-suppress-benzo-a-pyrene-induced-genotoxicity-in-vivo
#17
Kenichi Masumura, Naomi Toyoda-Hokaiwado, Naoko Niimi, Petr Grúz, Naoko A Wada, Akira Takeiri, Kou-Ichi Jishage, Masayuki Mishima, Takehiko Nohmi
DNA polymerase kappa (Polk) is a specialized DNA polymerase involved in translesion DNA synthesis. To understand the protective roles against genotoxins in vivo, we established inactivated Polk knock-in gpt delta (inactivated Polk KI) mice that possessed reporter genes for mutations and expressed inactive Polk. In this study, we examined genotoxicity of benzo[a]pyrene (BP) to determine whether Polk actually suppressed BP-induced genotoxicity as predicted by biochemistry and in vitro cell culture studies. Seven-week-old inactivated Polk KI and wild-type (WT) mice were treated with BP at doses of 5, 15, or 50 mg/(kg·day) for three consecutive days by intragastric gavage, and mutations in the colon and micronucleus formation in the peripheral blood were examined...
October 27, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/29073105/paf-promotes-stemness-and-radioresistance-of-glioma-stem-cells
#18
Derrick Sek Tong Ong, Baoli Hu, Yan Wing Ho, Charles-Etienne Gabriel Sauvé, Christopher A Bristow, Qianghu Wang, Asha S Multani, Peiwen Chen, Luigi Nezi, Shan Jiang, Claire Elizabeth Gorman, Marta Moreno Monasterio, Dimpy Koul, Matteo Marchesini, Simona Colla, Eun-Jung Jin, Erik P Sulman, Denise J Spring, Wai-Kwan Alfred Yung, Roel G W Verhaak, Lynda Chin, Y Alan Wang, Ronald A DePinho
An integrated genomic and functional analysis to elucidate DNA damage signaling factors promoting self-renewal of glioma stem cells (GSCs) identified proliferating cell nuclear antigen (PCNA)-associated factor (PAF) up-regulation in glioblastoma. PAF is preferentially overexpressed in GSCs. Its depletion impairs maintenance of self-renewal without promoting differentiation and reduces tumor-initiating cell frequency. Combined transcriptomic and metabolomic analyses revealed that PAF supports GSC maintenance, in part, by influencing DNA replication and pyrimidine metabolism pathways...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29073063/primpol-is-required-for-replication-reinitiation-after-mtdna-damage
#19
Rubén Torregrosa-Muñumer, Josefin M E Forslund, Steffi Goffart, Annika Pfeiffer, Gorazd Stojkovič, Gustavo Carvalho, Natalie Al-Furoukh, Luis Blanco, Sjoerd Wanrooij, Jaakko L O Pohjoismäki
Eukaryotic PrimPol is a recently discovered DNA-dependent DNA primase and translesion synthesis DNA polymerase found in the nucleus and mitochondria. Although PrimPol has been shown to be required for repriming of stalled replication forks in the nucleus, its role in mitochondria has remained unresolved. Here we demonstrate in vivo and in vitro that PrimPol can reinitiate stalled mtDNA replication and can prime mtDNA replication from nonconventional origins. Our results not only help in the understanding of how mitochondria cope with replicative stress but can also explain some controversial features of the lagging-strand replication...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29071010/error-prone-and-error-free-translesion-dna-synthesis-over-site-specifically-created-dna-adducts-of-aryl-hydrocarbons-3-nitrobenzanthrone-and-4-aminobiphenyl
#20
REVIEW
Takashi Yagi, Yoshihiro Fujikawa, Tomoko Sawai, Takeji Takamura-Enya, Sayoko Ito-Harashima, Masanobu Kawanishi
Aryl hydrocarbons such as 3-nitrobenzanthrone (NBA), 4-aminobiphenyl (ABP), acetylaminofluorene (AAF), benzo(a)pyrene (BaP), and 1-nitropyrene (NP) form bulky DNA adducts when absorbed by mammalian cells. These chemicals are metabolically activated to reactive forms in mammalian cells and preferentially get attached covalently to the N(2) or C8 positions of guanine or the N(6) position of adenine. The proportion of N(2) and C8 guanine adducts in DNA differs among chemicals. Although these adducts block DNA replication, cells have a mechanism allowing to continue replication by bypassing these adducts: translesion DNA synthesis (TLS)...
October 2017: Toxicological Research
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