Mutations occurring spontaneously or induced by environmental genotoxicants are a major initiating cause of cancer. Nearly all genotoxicant-induced mutations result from DNA damage and replication of the damaged DNA by specialized translesion synthesis (TLS) DNA polymerases that are less accurate than normal replicative DNA polymerases. The PI's laboratory has recently discovered that TLS DNA polymerase ??(Pol ?) also becomes a powerful source of spontaneous mutations in cells with defects in normal replication machinery. The mechanisms regulating the recruitment of Pol ? in response to replication defects, however, remain obscure. This proposal seeks to further investigate the novel role of Pol ? in mutagenesis in the absence of overt DNA damage. The long-term goal of this study is to define the mechanisms by which genetic and environmental factors regulate the contribution of error-prone DNA polymerases to mutagenesis. The yeast Saccharomyces cerevisiae model system will be utilized in the proposed studies, with the goal of using the data obtained in yeast to further advance our understanding of the mechanisms of mutagenesis in human cells.
The Specific Aims of this project are: (1) To define the role of TLS polymerases in the mutagenic response to replication defects;(2) To define the role of the polymerase accessory factor PCNA in the mutagenic response to replication defects;and (3) To determine the effects on the rate of mutation accumulation of a combination of the replication defects with environmental genotoxicant exposure. The proposed work will lead to a better understanding of the mechanisms by which DNA replication defects cause mutations. This information will be important for the development of effective approaches to cancer prevention, particularly in individuals carrying mutations or polymorphisms in DNA replication genes.

Public Health Relevance

Gene mutation is a key initiating step in the development of cancer. A major role in the generation of mutations is played by Pol ?. This proposal seeks to investigate the mechanisms that control the mutagenic activity of Pol ?. This research will lead to a better understanding of the events underlying the incidence of cancer, and, in the long run, help develop effective preventive approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015869-05
Application #
8463180
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Mcallister, Kimberly A
Project Start
2009-07-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$224,649
Indirect Cost
$73,370
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Kochenova, Olga V; Daee, Danielle L; Mertz, Tony M et al. (2015) DNA polymerase ζ-dependent lesion bypass in Saccharomyces cerevisiae is accompanied by error-prone copying of long stretches of adjacent DNA. PLoS Genet 11:e1005110
Mertz, Tony M; Sharma, Sushma; Chabes, Andrei et al. (2015) Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity. Proc Natl Acad Sci U S A 112:E2467-76
Kane, Daniel P; Shcherbakova, Polina V (2014) A common cancer-associated DNA polymerase ε mutation causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from loss of proofreading. Cancer Res 74:1895-901
Northam, Matthew R; Moore, Elizabeth A; Mertz, Tony M et al. (2014) DNA polymerases ýý and Rev1 mediate error-prone bypass of non-B DNA structures. Nucleic Acids Res 42:290-306
Kadyrova, Lyudmila Y; Mertz, Tony M; Zhang, Yu et al. (2013) A reversible histone H3 acetylation cooperates with mismatch repair and replicative polymerases in maintaining genome stability. PLoS Genet 9:e1003899
Shah, Kartik A; Shishkin, Alexander A; Voineagu, Irina et al. (2012) Role of DNA polymerases in repeat-mediated genome instability. Cell Rep 2:1088-95
Kochenova, O V; Soshkina, J V; Stepchenkova, E I et al. (2011) Participation of translesion synthesis DNA polymerases in the maintenance of chromosome integrity in yeast Saccharomyces cerevisiae. Biochemistry (Mosc) 76:49-60
Sharma, Neeru M; Kochenova, Olga V; Shcherbakova, Polina V (2011) The non-canonical protein binding site at the monomer-monomer interface of yeast proliferating cell nuclear antigen (PCNA) regulates the Rev1-PCNA interaction and Polζ/Rev1-dependent translesion DNA synthesis. J Biol Chem 286:33557-66
Pavlov, Youri I; Shcherbakova, Polina V (2010) DNA polymerases at the eukaryotic fork-20 years later. Mutat Res 685:45-53
Northam, Matthew R; Robinson, Heather A; Kochenova, Olga V et al. (2010) Participation of DNA polymerase zeta in replication of undamaged DNA in Saccharomyces cerevisiae. Genetics 184:27-42

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