Mechanisms and Functions of ATR signaling

Project Summary The premise of this application is that discovering the basic mechanisms and functions of replication stress signaling pathways will contribute to the development of effective cancer therapies. Specifically, our goal is to understand how the ATR (ATM and rad3-related) kinase promotes genome stability and how its inhibition could be useful as a cancer therapy. ATR functions at the apex of DNA damage and replication stress response pathways that are needed every cell division cycle to promote the complete and accurate duplication 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. Inhibiting ATR hypersensitizes cells to DNA damaging chemotherapies and targeted agents like PARP inhibitors. Thus, ATR may be a useful drug target and ATR inhibitors are currently in clinical trials in a variety of cancer settings. We previously defined how ATR is activated, identified critical targets to control DNA replication and cell division, and defined synthetic lethal opportunities where ATR inhibitors could be useful. In this proposal we will extend these studies to examine specific mechanisms of ATR action that promote the survival of cancer cells. We will define mechanisms for how ATR regulates DNA damage tolerance pathways, use unbiased approaches to expand our understanding of ATR-dependent regulation of replication stress responses, and study the unique functions of individual ATR activating proteins including ETAA1. 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 genome integrity and the mechanisms of action of ATR pathway inhibitors.