scholarly journals Polη, a Y-family translesion synthesis polymerase, promotes cellular tolerance of Myc-induced replication stress

2018 ◽  
Vol 131 (12) ◽  
pp. jcs212183 ◽  
Author(s):  
Kiminori Kurashima ◽  
Takayuki Sekimoto ◽  
Tsukasa Oda ◽  
Tsuyoshi Kawabata ◽  
Fumio Hanaoka ◽  
...  
Keyword(s):  
Translesion Synthesis ◽  
Replication Stress ◽  
Cellular Tolerance ◽  
Y Family

scholarly journals Y-family DNA polymerase-independent gap-filling translesion synthesis across aristolochic acid-derived adenine adducts in mouse cells

DNA Repair ◽  
2016 ◽  
Vol 46 ◽  
pp. 55-60 ◽  
Author(s):  
Keiji Hashimoto ◽  
Radha Bonala ◽  
Francis Johnson ◽  
Arthur P. Grollman ◽  
Masaaki Moriya
Keyword(s):  
Dna Polymerase ◽  
Aristolochic Acid ◽  
Translesion Synthesis ◽  
Gap Filling ◽  
Mouse Cells ◽  
Adenine Adducts ◽  
Y Family

scholarly journals Translesion Synthesis across Abasic Lesions by Human B-Family and Y-Family DNA Polymerases α, δ, η, ι, κ, and REV1

2010 ◽  
Vol 404 (1) ◽  
pp. 34-44 ◽  
Author(s):  
Jeong-Yun Choi ◽  
Seonhee Lim ◽  
Eun-Jin Kim ◽  
Ara Jo ◽  
F. Peter Guengerich
Keyword(s):  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Y Family

scholarly journals Implications of inhibition of Rev1 interaction with Y family DNA polymerases for cisplatin chemotherapy

2021 ◽  
Author(s):  
Jung-Hoon Yoon ◽  
Robert E. Johnson ◽  
Louise Prakash ◽  
Satya Prakash
Keyword(s):  
Adverse Effects ◽  
Cancer Cells ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Adduct ◽  
Secondary Malignancies ◽  
Normal Cells ◽  
Cross Links ◽  
Y Family

Chemotherapy with cisplatin becomes limiting due to toxicity and secondary malignancies. In principle, therapeutics could be improved by targeting translesion synthesis (TLS) polymerases (Pols) that promote replication through intrastrand cross-links, the major cisplatin-induced DNA adduct. However, to specifically target malignancies with minimal adverse effects on normal cells, a good understanding of TLS mechanisms in normal versus cancer cells is paramount. We show that in normal cells, TLS through cisplatin intrastrand cross-links is promoted by Polη- or Polι-dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Polζ. Our findings that a recently identified Rev1 inhibitor, JH-RE-06, purported to specifically disrupt Rev1 interaction with Polζ to block TLS through cisplatin adducts in cancer cells, abrogates Rev1's ability to function with Y family Pols as well, implying that by inactivating Rev1-dependent TLS in normal cells, this inhibitor will exacerbate the toxicity and tumorigenicity of chemotherapeutics with cisplatin.

scholarly journals Mechanism of Translesion Synthesis Past an Equine Estrogen-DNA Adduct by Y-Family DNA Polymerases

2007 ◽  
Vol 371 (5) ◽  
pp. 1151-1162 ◽  
Author(s):  
Manabu Yasui ◽  
Naomi Suzuki ◽  
Xiaoping Liu ◽  
Yoshinori Okamoto ◽  
Sung Yeon Kim ◽  
...  
Keyword(s):  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Adduct ◽  
Y Family

scholarly journals ATR-mediated phosphorylation of DNA polymerase η is needed for efficient recovery from UV damage

2011 ◽  
Vol 192 (2) ◽  
pp. 219-227 ◽  
Author(s):  
Thomas Göhler ◽  
Simone Sabbioneda ◽  
Catherine M. Green ◽  
Alan R. Lehmann
Keyword(s):  
Dna Damage ◽  
Dna Polymerase ◽  
Mammalian Cells ◽  
Translesion Synthesis ◽  
Physical Interaction ◽  
Uv Damage ◽  
Checkpoint Response ◽  
Ubiquitin Binding Domain ◽  
Efficient Recovery ◽  
Y Family

DNA polymerase η (polη) belongs to the Y-family of DNA polymerases and facilitates translesion synthesis past UV damage. We show that, after UV irradiation, polη becomes phosphorylated at Ser601 by the ataxia-telangiectasia mutated and Rad3-related (ATR) kinase. DNA damage–induced phosphorylation of polη depends on its physical interaction with Rad18 but is independent of PCNA monoubiquitination. It requires the ubiquitin-binding domain of polη but not its PCNA-interacting motif. ATR-dependent phosphorylation of polη is necessary to restore normal survival and postreplication repair after ultraviolet irradiation in xeroderma pigmentosum variant fibroblasts, and is involved in the checkpoint response to UV damage. Taken together, our results provide evidence for a link between DNA damage–induced checkpoint activation and translesion synthesis in mammalian cells.

scholarly journals Inhibition of the translesion synthesis polymerase REV1 exploits replication gaps as a cancer vulnerability

2020 ◽  
Vol 6 (24) ◽  
pp. eaaz7808 ◽  
Author(s):  
Sumeet Nayak ◽  
Jennifer A. Calvo ◽  
Ke Cong ◽  
Min Peng ◽  
Emily Berthiaume ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dna Damage ◽  
Stress Response ◽  
Cancer Cell ◽  
Small Molecule ◽  
Replication Fork ◽  
Translesion Synthesis ◽  
Replication Stress ◽  
Fiber Analysis ◽  
Molecule Inhibitor

The replication stress response, which serves as an anticancer barrier, is activated not only by DNA damage and replication obstacles but also oncogenes, thus obscuring how cancer evolves. Here, we identify that oncogene expression, similar to other replication stress–inducing agents, induces single-stranded DNA (ssDNA) gaps that reduce cell fitness. DNA fiber analysis and electron microscopy reveal that activation of translesion synthesis (TLS) polymerases restricts replication fork slowing, reversal, and fork degradation without inducing replication gaps despite the continuation of replication during stress. Consistent with gap suppression (GS) being fundamental to cancer, we demonstrate that a small-molecule inhibitor targeting the TLS factor REV1 not only disrupts DNA replication and cancer cell fitness but also synergizes with gap-inducing therapies such as inhibitors of ATR or Wee1. Our work illuminates that GS during replication is critical for cancer cell fitness and therefore a targetable vulnerability.

scholarly journals Cellular redox sensor HSCARG negatively regulates the translesion synthesis pathway and exacerbates mammary tumorigenesis

2019 ◽  
Vol 116 (51) ◽  
pp. 25624-25633 ◽  
Author(s):  
Weicheng Zang ◽  
Chuanzhen Yang ◽  
Tingting Li ◽  
Liming Liao ◽  
Xiaofeng Zheng
Keyword(s):  
Translesion Synthesis ◽  
Mammary Tumorigenesis ◽  
Strand Break ◽  
Redox Status ◽  
Regulatory Function ◽  
Cellular Redox ◽  
Redox Sensor ◽  
Dna Double Strand Break ◽  
Damage Response ◽  
Y Family

The translesion synthesis (TLS) pathway is a double-edged sword in terms of genome integrity. Deficiency in TLS leads to generation of DNA double strand break (DSB) during replication stress, while excessive activation of the TLS pathway increases the risk of point mutation. Here we demonstrate that HSCARG, a cellular redox sensor, directly interacts with the key protein PCNA in the TLS pathway. HSCARG enhances the interaction between PCNA and the deubiquitinase complex USP1/UAF1 and inhibits the monoubiquitination of PCNA, thereby impairing the recruitment of Y-family polymerases and increasing cell sensitivity to stimuli that trigger replication fork blockades. In response to oxidative stress, disaggregation of HSCARG dimers into monomers and the nuclear transport of HSCARG activate the regulatory function of HSCARG in the TLS pathway. Moreover, HSCARG, which is highly expressed in breast carcinoma, promotes the accumulation of DSBs and mutations. HSCARG knockout PyMT transgenic mice exhibit delayed mammary tumorigenesis compared with that in HSCARG wild-type or heterozygous PyMT mice. Taken together, these findings expand our understanding of TLS regulatory mechanisms and establish a link between the cellular redox status and the DNA damage response (DDR).

scholarly journals A DinB Ortholog Enables Mycobacterial Growth under dTTP-Limiting Conditions Induced by the Expression of a Mycobacteriophage-Derived Ribonucleotide Reductase Gene

2015 ◽  
Vol 198 (2) ◽  
pp. 352-362 ◽  
Author(s):  
Shreya Ghosh ◽  
Sourabh Samaddar ◽  
Prithwiraj Kirtania ◽  
Sujoy K. Das Gupta
Keyword(s):  
Dna Repair ◽  
Growth Inhibition ◽  
Ribonucleotide Reductase ◽  
Translesion Synthesis ◽  
Inhibitory Effect ◽  
Limiting State ◽  
Content Type ◽  
Y Family

ABSTRACTMycobacteriumspecies such asM. smegmatisandM. tuberculosisencode at least two translesion synthesis (TLS) polymerases, DinB1 and DinB2, respectively. Although predicted to be linked to DNA repair, their rolein vivoremains enigmatic.M. smegmatismc2155, a strain commonly used to investigate mycobacterial genetics, has two copies ofdinB2, the gene that codes for DinB2, by virtue of a 56-kb chromosomal duplication. Expression of a mycobacteriophage D29 gene (gene 50) encoding a class II ribonucleotide reductase inM. smegmatisΔDRKIN, a strain derived from mc2155 in which one copy of the duplication is lost, resulted in DNA replication defects and growth inhibition. The inhibitory effect could be linked to the deficiency of dTTP that resulted under these circumstances. The selective inhibition observed in the ΔDRKIN strain was found to be due solely to a reduced dosage ofdinB2in this strain.Mycobacterium bovis, which is closely related toM. tuberculosis, the tuberculosis pathogen, was found to be highly susceptible to gene 50 overexpression. Incidentally, these slow-growing pathogens harbor one copy ofdinB2. The results indicate that the induction of a dTTP-limiting state can lead to growth inhibition in mycobacteria, with the effect being maximum in cells deficient in DinB2.IMPORTANCEMycobacteriumspecies, such asM. tuberculosis, the tuberculosis pathogen, are known to encode several Y family DNA polymerases, one of which is DinB2, an ortholog of the DNA repair-related protein DinP ofEscherichia coli. Although this protein has been biochemically characterized previously and found to be capable of translesion synthesisin vitro, itsin vivofunction remains unknown. Using a novel method to induce dTTP deficiency in mycobacteria, we demonstrate that DinB2 can aid mycobacterial survival under such conditions. Apart from unraveling a specific role for the mycobacterial Y family DNA polymerase DinB2 for the first time, this study also paves the way for the development of drugs that can kill mycobacteria by inducing a dTTP-deficient state.

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