Genomic instability is a hallmark of cancer. The maintenance of genomic stability relies on the concerted action of a number of cellular processes, such as DNA replication, DNA repair, and cell-cycle transitions. The central coordinator of these cellular processes is the DNA damage-signaling pathway, which is often referred to as the checkpoint. In human cells, the checkpoint is orchestrated by two master kinases, ATM and ATR. While ATM is critical for the response to DNA double-stranded breaks (DSBs), ATR responds to a much broader spectrum of DNA damage and DNA replication problems. How ATR is activated by various forms of DNA damage and replication stress is a fundamental question for the research of genome maintenance. ATR forms a complex with ATRIP in human cells. We and others have shown that single-stranded DNA (ssDNA) coated by RPA is the key structure at sites of DNA damage and stressed replication forks that recruits and activates ATR-ATRIP. Nevertheless, how exactly ATR-ATRIP is activated on RPA-ssDNA and how it regulates DNA repair is still poorly understood. In this study, we have found that ATRIP is SUMOylated in a DNA damage-stimulated manner, and that ATRIP SUMOylation plays a key role in ATR activation. Furthermore, we have identified a novel function of ATR in homologous recombination (HR), providing a critical clue to the role for ATR in DNA repair. Mostly excitingly, we found that cancer cells with specific genetic alterations are addicted to the HR pathway and highly sensitive to ATR inhibitors, presenting a conceptually new way to target ATR in cancer therapy. In this application, we propose to address (1) how ATRIP SUMOylation drives ATR activation, (2) how ATR regulates HR, and (3) how to target ATR in cancers. If successful, our studies will greatly advance our understanding of the mechanism of ATR activation, the role for ATR in DNA repair, and the potential of ATR as a therapeutic target. Our research may ultimately bring the mechanistic studies on ATR to the rational use of ATR inhibitors in targeted cancer therapy.

Public Health Relevance

Genomic instability is a hallmark of cancer and an attractive target for therapy. We will investigate how ATR, a master DNA damage-signaling kinase in human cells, is activated by DNA damage and how it regulates DNA repair. Furthermore, we will explore how to attack specific vulnerabilities of cancer cells by inhibiting ATR.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics B Study Section (MGB)
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Willis, Kristine Amalee
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Massachusetts General Hospital
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