The long-term goal of the proposed research is to understand how cells preserve genome integrity during DNA replication. Specifically, this application focuses on the ATR (ATM and rad3-related) signaling pathway. ATR functions at the apex of a DNA damage and replication stress response pathway that is needed every cell division cycle to promote the complete and accurate replication of the genome. Many cancer cells are highly dependent on ATR function for proliferation and viability because of elevated levels of oncogene-induced replication stress and mutations in other genome maintenance pathways. Thus, ATR may be a useful drug target based on a synthetic lethal approach. In this proposal we test a specific model of how ATR promotes replication fork stabilization and repair, define the consequences of acute ATR inhibition on DNA replication and cell fate outcomes, define and characterize new ATR-regulated proteins that act at damaged replication forks, characterize cancer settings in which ATR inhibition might be useful using synthetic lethality, and test a new model of how ATR is regulated by autophosphorylation. This is a focused proposal aimed at understanding the most important and least understood aspects of ATR function. Specific hypotheses and innovative concepts based on preliminary data are tested using advanced biochemical and genetic approaches. In addition, the aims provide opportunities for unexpected discoveries about the mechanisms that maintain the genome during DNA replication and when ATR pathway inhibitors may be useful in the cancer clinic.

Public Health Relevance

The replication stress response controlled by the ATR kinase is essential to maintain genome integrity and prevent carcinogenesis. ATR pathway inhibitors are currently being developed as anti-cancer agents. This research proposal will define mechanisms by which ATR promotes genome maintenance during DNA replication and identify cellular consequences of acute disruption of this pathway.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Pelroy, Richard
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Vanderbilt University Medical Center
Schools of Medicine
United States
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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
Sirbu, Bianca M; Cortez, David (2013) DNA damage response: three levels of DNA repair regulation. Cold Spring Harb Perspect Biol 5:a012724
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