Polymerase Beta Variants and Cancer. Abstract: DNA polymerase beta functions in base excision repair (BER) which is important for the repair of endogenous DNA damage and damage caused by agents such as ionizing radiation. The broad long-term objective of the proposed research is to understand how aberrant BER is linked to carcinogenesis and the treatment of cancer with agents including ionizing radiation. The application consists of three specific aims.
The first aim i s to test the hypothesis that a cancer-associated variant of Pol beta induces tumorigenesis in mice.
The second aim i s to test the hypothesis that a germline variant of Pol beta is linked to cancer. For these aims we will characterize spontaneous and induced tumorigenesis and mutagenesis. We have recently identified colon tumor variants of Pol beta and the third aim is to test the hypothesis that these variants are linked to cancer. We will employ the focus formation and anchorage independent growth assays to characterize cellular transformation. Genomic instability will be assessed using the cII and chromosomal aberration assays. The significance of these studies lies in understanding the role of BER as a tumor suppressor mechanism.

Public Health Relevance

The goal of this application is to determine how variants of the DNA polymerase beta gene found in people and their tumors are linked to cancer. This is important because it has the potential to provide insights into how cancer is initiated and progresses and how it becomes resistant to various cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019179-03
Application #
8252218
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Reinlib, Leslie J
Project Start
2010-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$368,201
Indirect Cost
$145,451
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Lokanga, Rachel Adihe; Senejani, Alireza Ghodsi; Sweasy, Joann Balazs et al. (2015) Heterozygosity for a hypomorphic Polβ mutation reduces the expansion frequency in a mouse model of the Fragile X-related disorders. PLoS Genet 11:e1005181
Nemec, Antonia A; Murphy, Drew L; Donigan, Katherine A et al. (2014) The S229L colon tumor-associated variant of DNA polymerase β induces cellular transformation as a result of decreased polymerization efficiency. J Biol Chem 289:13708-16
Kidane, Dawit; Chae, Wook Jin; Czochor, Jennifer et al. (2014) Interplay between DNA repair and inflammation, and the link to cancer. Crit Rev Biochem Mol Biol 49:116-39
Senejani, Alireza G; Liu, Yanfeng; Kidane, Dawit et al. (2014) Mutation of POLB causes lupus in mice. Cell Rep 6:1-8
Ray, Sreerupa; Menezes, Miriam Rose; Senejani, Alireza et al. (2013) Cellular roles of DNA polymerase beta. Yale J Biol Med 86:463-9
Senejani, Alireza G; Dalal, Shibani; Liu, Yanfeng et al. (2012) Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates. Proc Natl Acad Sci U S A 109:6632-7
Murphy, Drew L; Donigan, Katherine A; Jaeger, Joachim et al. (2012) The E288K colon tumor variant of DNA polymerase ýý is a sequence specific mutator. Biochemistry 51:5269-75