The long-term goal of the proposed research is to understand how cells preserve genome integrity. 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 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. Thus, ATR may be a useful drug target based on a synthetic lethal approach. ATR inhibitors are currently in clinical trials in a variety of cancer settings. We previously found that there are two independent ATR signaling complexes formed by TOPBP1 or ETAA1. In this proposal we examine the functions of these alternative ATR complexes, explore how these proteins activate ATR, and examine how ATR is regulated in response to different types of replication challenges. 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 and when ATR pathway inhibitors may be useful in the cancer clinic.
/Relevance The DNA damage response controlled by the ATR kinase is essential to maintain genome integrity and prevent cancer. ATR signaling inhibitors are currently being developed as anti-cancer agents. By defining mechanisms by which ATR promotes genome stability and identifying cellular consequences of inhibiting ATR, this project will help the development of ATR inhibitors as effective cancer therapies.
