Despite rapid progress in defining distinct DNA repair pathways over the past few years, our knowledge of p53-binding protein 1 (53BP1) in DNA repair remains incomplete. My laboratory is interested in elucidating the molecular mechanisms underlying genomic instability and tumorigenesis. Since I started my laboratory in 1999, we have discovered and characterized many essential DNA damage checkpoint and repair proteins. Our long-term goal is to reveal the complex regulation of the DNA repair network, which will permit us to meaningfully contribute to cancer biology and treatment. This proposal focuses on 53BP1, a key component in DNA repair. Many years ago, our group was one of the first to demonstrate the role of 53BP1 in DNA damage response. We established the first 53bp1 knockout mice and revealed that 53BP1 is required for DNA repair and acts as a tumor suppressor in vivo. In addition, we elucidated the regulation of 53BP1 after DNA damage. In particular, over the past decade, we and others demonstrated that the H2AX-dependent DNA damage signaling pathway, composed of H2AX, MDC1, RNF8, and RNF168, controls the recruitment and accumulation of 53BP1 at sites of DNA breaks. In particular, we showed that 53BP1, because of its role in DNA repair, is critical for a particular repair process called class- switch recombination, indicating that 53BP1 is involved in a special DNA repair pathway that is distinctly different from the canonical nonhomologous end-joining (NHEJ) pathway. Moreover, our recent studies and those of others suggest that 53BP1 controls two downstream sub-pathways and suppresses homologous recombination (HR) repair in BRCA1-deficient cells, which is critically important for response to cancer therapies based on poly (ADP-ribose) polymerase inhibitors (PARPi). Together, these data highlight the existence of a bona fide 53BP1-dependent repair pathway that has not been thoroughly investigated. Our goals in this proposal are to further understand the 53BP1-dependent repair pathway and reveal mechanistically how it counteracts the HR repair pathway in response to DNA damage. To achieve these goals, we propose the following specific aims: 1) delineate the 53BP1-dependent end- joining repair pathway; 2) elucidate the molecular mechanisms underlying the regulation and function of the RIF1-REV7 branch of the 53BP1-dependent repair pathway; and 3) reveal mechanistically how the HR pathway operates in the absence of BRCA1 and 53BP1. These proposed studies are significant because they not only will elucidate the 53BP1-dependent repair pathway in the complex DNA repair network, but also will provide ways to overcome therapy resistance for cancer patients.
It is established that redundant and overlapping DNA repair pathways are essential for genome maintenance and cell survival. However, little is known about the competition and/or counteraction of the various repair mechanisms, which are best exemplified by the relationship between 53BP1 and BRCA1. The proposed research is relevant to public health because we will further elucidate the 53BP1-dependent DNA repair pathway and reveal the mechanisms by which it counteracts homologous recombination repair in BRCA1- deficient cells and therefore is responsible for PARPi sensitivity in cancer therapy.