Abstract 4089: Investigating translesion synthesis DNA polymerases roles on tumor protection after temozolomide induced DNA damage

2020 ◽  
Author(s):  
Marcela Teatin Latancia ◽  
André Uchimura Bastos ◽  
Natália Cestari Moreno ◽  
Davi Jardim ◽  
Clarissa RR Rocha ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Tumor Protection

scholarly journals Beyond the Lesion: Back to High Fidelity DNA Synthesis

2022 ◽  
Vol 8 ◽  
Author(s):  
Joseph D. Kaszubowski ◽  
Michael A. Trakselis
Keyword(s):  
Dna Damage ◽  
Dna Synthesis ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Structural Features ◽  
Dna Bases ◽  
High Fidelity ◽  
Nucleotide Incorporation ◽  
Hand Off ◽  
Enzymatic Mechanisms

High fidelity (HiFi) DNA polymerases (Pols) perform the bulk of DNA synthesis required to duplicate genomes in all forms of life. Their structural features, enzymatic mechanisms, and inherent properties are well-described over several decades of research. HiFi Pols are so accurate that they become stalled at sites of DNA damage or lesions that are not one of the four canonical DNA bases. Once stalled, the replisome becomes compromised and vulnerable to further DNA damage. One mechanism to relieve stalling is to recruit a translesion synthesis (TLS) Pol to rapidly synthesize over and past the damage. These TLS Pols have good specificities for the lesion but are less accurate when synthesizing opposite undamaged DNA, and so, mechanisms are needed to limit TLS Pol synthesis and recruit back a HiFi Pol to reestablish the replisome. The overall TLS process can be complicated with several cellular Pols, multifaceted protein contacts, and variable nucleotide incorporation kinetics all contributing to several discrete substitution (or template hand-off) steps. In this review, we highlight the mechanistic differences between distributive equilibrium exchange events and concerted contact-dependent switching by DNA Pols for insertion, extension, and resumption of high-fidelity synthesis beyond the lesion.

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

KGF facilitates repair of radiation-induced DNA damage in alveolar epithelial cells

1997 ◽  
Vol 272 (6) ◽  
pp. L1174-L1180 ◽  
Author(s):  
M. Takeoka ◽  
W. F. Ward ◽  
H. Pollack ◽  
D. W. Kamp ◽  
R. J. Panos
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Epithelial Cells ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Alveolar Epithelial ◽  
Radiation Induced ◽  
Dna Strand

Administration of exogenous keratinocyte growth factor (KGF) prevents or attenuates several forms of oxidant-mediated lung injury. Because DNA damage in epithelial cells is a component of radiation pneumotoxicity, we determined whether KGF ameliorated DNA strand breaks in irradiated A549 cells. Cells were exposed to 137Cs gamma rays, and DNA damage was measured by alkaline unwinding and ethidium bromide fluorescence after a 30-min recovery period. Radiation induced a dose-dependent increase in DNA strand breaks. The percentage of double-stranded DNA after exposure to 30 Gy increased from 44.6 +/- 3.5% in untreated control cells to 61.6 +/- 5.0% in cells cultured with 100 ng/ml KGF for 24 h (P < 0.05). No reduction in DNA damage occurred when the cells were cultured with KGF but maintained at 0 degree C during and after irradiation. The sparing effect of KGF on radiation-induced DNA damage was blocked by aphidicolin, an inhibitor of DNA polymerases-alpha, -delta, and -epsilon and by butylphenyl dGTP, which blocks DNA polymerase-alpha strongly and polymerases-delta and -epsilon less effectively. However, dideoxythymidine triphosphate, a specific inhibitor of DNA polymerase-beta, did not abrogate the KGF effect. Thus KGF increases DNA repair capacity in irradiated pulmonary epithelial cells, an effect mediated at least in part by DNA polymerases-alpha, -delta, and -epsilon. Enhancement of DNA repair capability after cell damage may be one mechanism by which KGF is able to ameliorate oxidant-mediated alveolar epithelial injury.

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

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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