The broad, long-term objective of the proposed research is to determine if alterations in base excision repair (BER) genes that exist in the normal population and in tumors lead to phenotypes that could be linked to the etiology of cancer or to treatment response.
The specific aims of the application are to test the hypothesis that polymorphisms in BER genes lead to cellular transformation, to test the hypothesis that BER variants arising in the normal population and in tumors lead to genomic instability, and to test the hypothesis that BER protein variants affect cancer treatment. To test these hypotheses we will take a combined genetic and biochemical approach. We will express the variant BER proteins in cells and determine whether they induce focus formation, anchorage independent growth, and tumors in mice. We will determine if expression of the variants in cells induces mutations, and characterizethe types of mutations they induce. We will determine if the variants are differentially sensitive to various cancer treatments, including ionizing radiation and alkylating agents, the latter in collaboration with Project 1. We will also characterize the drug sensitivity of cells in which multiple DMA repair pathways are compromised, in collaboration with Projects 1, 2, and 4. This proposal has the potential to further our understanding of the relationship between BER variants and cancer etiology, and to provide mechanistic insights into the role of aberrant BER in cancer onset and treatment. Because BER is responsible for the repair of 10,000 lesions per cell per day and is a highly coordinated process, we suspect that even minor imbalances in this system will impact cancer etiology. A thorough understanding of BER variants in people will also serve as the basis for a future study of environmental aspects of cancer promotion and progression within the context of these BER variants and has the potential to provide important insight on lifestyle choices regarding cancer prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA129186-05S1
Application #
8518510
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$6,919
Indirect Cost
$2,752
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Penketh, P G; Shyam, K; Baumann, R P et al. (2015) A simple and inexpensive method to control oxygen concentrations within physiological and neoplastic ranges. Anal Biochem 491:1-3
Penketh, Philip G; Shyam, Krishnamurthy; Zhu, Rui et al. (2014) Influence of phosphate and phosphoesters on the decomposition pathway of 1,2-bis(methylsulfonyl)-1-(2-chloroethyhydrazine (90CE), the active anticancer moiety generated by Laromustine, KS119, and KS119W. Chem Res Toxicol 27:818-33
Penketh, Philip G; Patridge, Eric; Shyam, Krishnamurthy et al. (2014) Influence of glutathione and glutathione S-transferases on DNA interstrand cross-link formation by 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine, the active anticancer moiety generated by laromustine. Chem Res Toxicol 27:1440-9
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Lamb, Kristy L; Liu, Yanfeng; Ishiguro, Kimiko et al. (2014) Tumor-associated mutations in Oýýý -methylguanine DNA-methyltransferase (MGMT) reduce DNA repair functionality. Mol Carcinog 53:201-10
Zhu, Rui; Baumann, Raymond P; Penketh, Philip G et al. (2013) Hypoxia-selective O6-alkylguanine-DNA alkyltransferase inhibitors: design, synthesis, and evaluation of 6-(benzyloxy)-2-(aryldiazenyl)-9H-purines as prodrugs of O6-benzylguanine. J Med Chem 56:1355-9
Zhu, Rui; Baumann, Raymond P; Patridge, Eric et al. (2013) Chloroethylating and methylating dual function antineoplastic agents display superior cytotoxicity against repair proficient tumor cells. Bioorg Med Chem Lett 23:1853-9
Daley, James M; Niu, Hengyao; Sung, Patrick (2013) Roles of DNA helicases in the mediation and regulation of homologous recombination. Adv Exp Med Biol 767:185-202
Daley, James M; Sung, Patrick (2013) RIF1 in DNA break repair pathway choice. Mol Cell 49:840-1

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