scholarly journals Translesion synthesis DNA polymerases promote error-free replication through the minor-groove DNA adduct 3-deaza-3-methyladenine

2017 ◽  
Vol 292 (45) ◽  
pp. 18682-18688 ◽  
Author(s):  
Jung-Hoon Yoon ◽  
Jayati Roy Choudhury ◽  
Jeseong Park ◽  
Satya Prakash ◽  
Louise Prakash
Keyword(s):  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Minor Groove ◽  
Dna Adduct

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

Translesion Synthesis past 2′-Deoxyxanthosine, a Nitric Oxide-derived DNA Adduct, by Mammalian DNA Polymerases

2004 ◽  
Vol 344 (3) ◽  
pp. 665-674 ◽  
Author(s):  
Manabu Yasui ◽  
Naomi Suzuki ◽  
Holly Miller ◽  
Tomonari Matsuda ◽  
Saburo Matsui ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Adduct

scholarly journals A Role for Yeast and Human Translesion Synthesis DNA Polymerases in Promoting Replication through 3-Methyl Adenine

2007 ◽  
Vol 27 (20) ◽  
pp. 7198-7205 ◽  
Author(s):  
Robert E. Johnson ◽  
Sung-Lim Yu ◽  
Satya Prakash ◽  
Louise Prakash
Keyword(s):  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Minor Groove ◽  
Yeast Cells ◽  
Template Switching ◽  
Genetic Studies ◽  
Dna Lesion ◽  
A Minor ◽  
High Degree ◽  
Dependent Pathway

ABSTRACT 3-Methyl adenine (3meA), a minor-groove DNA lesion, presents a strong block to synthesis by replicative DNA polymerases (Pols). To elucidate the means by which replication through this DNA lesion is mediated in eukaryotic cells, here we carry out genetic studies in the yeast Saccharomyces cerevisiae treated with the alkylating agent methyl methanesulfonate. From the studies presented here, we infer that replication through the 3meA lesion in yeast cells can be mediated by the action of three Rad6-Rad18-dependent pathways that include translesion synthesis (TLS) by Polη or -ζ and an Mms2-Ubc13-Rad5-dependent pathway which presumably operates via template switching. We also express human Pols ι and κ in yeast cells and show that they too can mediate replication through the 3meA lesion in yeast cells, indicating a high degree of evolutionary conservation of the mechanisms that control TLS in yeast and human cells. We discuss these results in the context of previous observations that have been made for the roles of Pols η, ι, and κ in promoting replication through the minor-groove N2-dG adducts.

Miscoding Properties of 2′-Deoxyinosine, a Nitric Oxide-Derived DNA Adduct, during Translesion Synthesis Catalyzed by Human DNA Polymerases

2008 ◽  
Vol 377 (4) ◽  
pp. 1015-1023 ◽  
Author(s):  
Manabu Yasui ◽  
Emi Suenaga ◽  
Naoki Koyama ◽  
Chikahide Masutani ◽  
Fumio Hanaoka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Adduct ◽  
Human Dna

scholarly journals Role of Translesion Synthesis DNA Polymerases in DNA Replication in the Presence of a Weak DNA Polymerase δ in Saccharomyces cerevisiae

2018 ◽  
Vol 8 (2) ◽  
pp. 754-754
Author(s):  
Likui Zhang ◽  
Yanchao Huang ◽  
Xinyuan Zhu ◽  
Yuxiao Wang ◽  
Haoqiang Shi ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Replication ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Polymerase Δ

Frameshifts and deletions during in vitro translesion synthesis past Pt–DNA adducts by DNA polymerases β and η

DNA Repair ◽  
2002 ◽  
Vol 1 (12) ◽  
pp. 1003-1016 ◽  
Author(s):  
Ekaterina Bassett ◽  
Alexandra Vaisman ◽  
Kristen A. Tropea ◽  
Chad M. McCall ◽  
Chikahide Masutani ◽  
...  
Keyword(s):  
Dna Adducts ◽  
Dna Polymerases ◽  
Translesion Synthesis

Translesion Synthesis past Equine Estrogen-Derived 2‘-Deoxycytidine DNA Adducts by Human DNA Polymerases η and κ†

Biochemistry ◽  
2004 ◽  
Vol 43 (35) ◽  
pp. 11312-11320 ◽  
Author(s):  
Naomi Suzuki ◽  
Manabu Yasui ◽  
Y. R. Santosh Laxmi ◽  
Haruo Ohmori ◽  
Fumio Hanaoka ◽  
...  
Keyword(s):  
Dna Adducts ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Human Dna

Tissue methylation and demethylation influence translesion synthesis DNA polymerases (TLS) contributing to the genesis of chromosomal abnormalities in myelodysplastic syndrome

2020 ◽  
pp. jclinpath-2020-207131
Author(s):  
Gabrielle Melo Cavalcante ◽  
Daniela Paula Borges ◽  
Roberta Taiane Germano de Oliveira ◽  
Cristiana Libardi Miranda Furtado ◽  
Ana Paula Negreiros Nunes Alves ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Chromosomal Abnormalities ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Normal Karyotype ◽  
Dna Demethylation ◽  
Repair System ◽  
Low Expression

AimsDNA methylation has its distribution influenced by DNA demethylation processes with the catalytic conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Myelodysplastic syndrome (MDS) has been associated with epigenetic dysregulation of genes related to DNA repair system, chronic immune response and cell cycle.MethodsWe evaluated the tissue DNA methylation/hydroxymethylation in bone marrow trephine biopsies of 73 patients with MDS, trying to correlate with the mRNA expression of 21 genes (POLH, POLL, REV3L, POLN, POLQ, POLI, POLK, IRF-1, IRF-2, IRF-3, IRF-4, IRF-5, IRF6, IRF-7, IRF-8,IRF-9, MAD2, CDC20, AURKA, AURKB and TPX2).ResultsThe M-score (5mC) was significantly higher in patients with chromosomal abnormalities than patients with normal karyotype (95% CI –27.127779 to –2.368020; p=0.022). We observed a higher 5mC/5hmC ratio in patients classified as high-risk subtypes compared with low-risk subtypes (95% CI –72.922115 to –1.855662; p=0.040) as well as patients with hypercellular bone marrow compared with patients with normocellular/hypocellular bone marrow (95% CI –69.189259 to –0.511828; p=0.047) and with the presence of dyserythropoiesis (95% CI 17.077703 to 51.331388; p=0.001). DNA pols with translesion activity are significantly influenced by methylation. As 5mC immunoexpression increases, the expressions of POLH (r=−0.816; r2 =0.665; p=0.000), POLQ (r=−0.790; r2=0.624; p=0.001), PCNA (r=−0.635; r2=0.403; p=0.020), POLK (r=−0.633; r2=0.400; p=0.036 and REV1 (r=−0.578; r2=0.334; p=0.049) decrease.ConclusionsOur results confirm that there is an imbalance in the DNA methylation in MDS, influencing the development of chromosomal abnormalities which may be associated with the low expression of DNA polymerases with translesion synthesis polymerases activity.

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