The long-term goal of the proposed research is to understand how cells preserve genomic integrity. Genetic instability is one characteristic of cancer cells and explains how they accumulate multiple genetic alterations that promote tumorigenic growth. Cells with defective DNA damage and replication stress response capabilities exhibit high rates of genomic instability. Therefore, we aim to define the components of DNA damage/replication stress response pathways and determine how they work cooperatively to prevent cancer by regulating the cell cycle, promoting DNA repair or initiating apoptosis. The ATR (ATM and rad3-related) kinase functions at the apex of a DNA damage and replication stress response pathway. In the previous funding period, we defined several mechanisms by which the ATR-interacting protein (ATRIP) promotes ATR specific responses to genotoxic stress. Our results as well as those of other researchers suggest a multi-step model for ATR signaling regulation, but many questions remain unanswered. We hypothesize that ATR-ATRIP activation in response to genotoxic stress is regulated through multiple mechanisms including RPA-dependent localization, TopBP1 binding, and phosphorylation. This hypothesis will be tested using a combination of biochemical and genetic approaches. Components of the ATR signaling pathway are frequently mutated in several human diseases;ATR activation is a major cellular response to most commonly used cancer therapies;and the ATR pathway is expected to be a useful drug target. Therefore, these mechanistic studies focus on highly significant biological questions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Molecular Genetics B Study Section (MGB)
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Pelroy, Richard
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Vanderbilt University Medical Center
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Badu-Nkansah, Akosua; Mason, Aaron C; Eichman, Brandt F et al. (2016) Identification of a Substrate Recognition Domain in the Replication Stress Response Protein Zinc Finger Ran-binding Domain-containing Protein 3 (ZRANB3). J Biol Chem 291:8251-7
Dungrawala, Huzefa; Rose, Kristie L; Bhat, Kamakoti P et al. (2015) The Replication Checkpoint Prevents Two Types of Fork Collapse without Regulating Replisome Stability. Mol Cell 59:998-1010
Carroll, Clinton; Hunley, Tracy E; Guo, Yan et al. (2015) A novel splice site mutation in SMARCAL1 results in aberrant exon definition in a child with Schimke immunoosseous dysplasia. Am J Med Genet A 167A:2260-4
Kavanaugh, Gina; Ye, Fei; Mohni, Kareem N et al. (2015) A whole genome RNAi screen identifies replication stress response genes. DNA Repair (Amst) 35:55-62
Kavanaugh, Gina; Zhao, Runxiang; Guo, Yan et al. (2015) Enhancer of Rudimentary Homolog Affects the Replication Stress Response through Regulation of RNA Processing. Mol Cell Biol 35:2979-90
Mohni, Kareem N; Thompson, Petria S; Luzwick, Jessica W et al. (2015) A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments. PLoS One 10:e0125482
Cortez, David (2015) Preventing replication fork collapse to maintain genome integrity. DNA Repair (Amst) 32:149-57
Sowd, Gregory A; Mody, Dviti; Eggold, Joshua et al. (2014) SV40 utilizes ATM kinase activity to prevent non-homologous end joining of broken viral DNA replication products. PLoS Pathog 10:e1004536
Frank, Andreas O; Vangamudi, Bhavatarini; Feldkamp, Michael D et al. (2014) Discovery of a potent stapled helix peptide that binds to the 70N domain of replication protein A. J Med Chem 57:2455-61
Mohni, Kareem N; Kavanaugh, Gina M; Cortez, David (2014) ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency. Cancer Res 74:2835-45

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