This is an application for a new Program Project grant entitled, """"""""DNA Repair in Cancer Biology and Therapy."""""""" This is a laboratory-based, basic science program that features four inter-related projects that stress fundamental aspects of DNA repair, genome stability, cancer biology and tumor hypoxia, with a key long-term goal of developing novel anti-cancer therapies that target interconnected DNA repair pathways and/or exploit tumor hypoxia. Dr. Sartorelli will develop novel hypoxia-activated prodrugs that are designed to inhibit the repair factor, O6-alkylguanine-DNA alkyltransferase (AGT), as well as prodrugs that, upon activation in hypoxic cells, will damage and crosslink DNA. Dr. Glazer, the PI, will lead a project that focuses on the transcriptional regulation of the homology-dependent repair (HDR) genes, RAD51 and BRCA1, in hypoxic cancer cells. This project will probe how HDR is regulated in hypoxic cancer cells and will test the extent to which this regulation of HDR may render such cells vulnerable to agents that target interconnected repair pathways. Dr. Sweasy will study how repair factors in the base excision repair (BER) pathway vary in the normal population and in tumors. She will examine the phenotypes of BER variants in cells in culture and in mice using assays for mutagenesis, genetic instability, transformation, and tumor formation. She will examine how deficiencies in BER may play into the HDR pathway to guide the design of new cancer therapies. Dr. Sung will study how the HDR pathway is regulated at the level of protein-protein interactions, with a focus on the repair factors, BRCA2, FANCD2, and RAD51. One administrative and two scientific cores will provide essential services to the program. The Project leaders and Core directors are joined by common interests, a history of collaboration, and joint efforts in teaching and training that provide cohesiveness in support of this effort. The overall Program represents a significant commitment of the Yale University School of Medicine and the participating investigators to studies that have direct relevance to cancer biology and therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S (M1))
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Pelroy, Richard
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Yale University
Schools of Medicine
New Haven
United States
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Penketh, Philip G; Shyam, Krishnamurthy; Baumann, Raymond P et al. (2016) When alcohol is the answer: Trapping, identifying and quantifying simple alkylating species in aqueous environments. Anal Biochem 508:34-7
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
Lin, Z Ping; Ratner, Elena S; Whicker, Margaret E et al. (2014) Triapine disrupts CtIP-mediated homologous recombination repair and sensitizes ovarian cancer cells to PARP and topoisomerase inhibitors. Mol Cancer Res 12:381-393
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
Lamb, Kristy L; Liu, Yanfeng; Ishiguro, Kimiko et al. (2014) Tumor-associated mutations in O? -methylguanine DNA-methyltransferase (MGMT) reduce DNA repair functionality. Mol Carcinog 53:201-10
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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Sjolund, Ashley B; Senejani, Alireza G; Sweasy, Joann B (2013) MBD4 and TDG: multifaceted DNA glycosylases with ever expanding biological roles. Mutat Res 743-744:12-25

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