BRCA1, a well-known tumor suppressor gene, exhibits significant ubiquitin (Ub) ligase activity in concert with BARD1. Although it is known that the BRCA1/BARD1 Ub ligase plays important roles during DNA damage response (DDR), very little is known about the identity of BRCA1/BARD1 cellular targets, how these targets are chosen, and the mechanism by which they are recruited to DNA damage sites. We were the first to demonstrate that BRCA1/BARD1 complex regulates mRNA 3? processing by its interaction with the m factor CstF-50 during DDR. We recently found, to our surprise, that CstF-50 can interact not only with BRCA1/BARD1 but also with some of its substrates, such as RNA polymerase II and histones. Moreover, CstF-50 can also interact with Ub. Importantly, CstF-50 can regulate BRCA1/BARD1-mediated ubiquitination. This is a novel regulatory function for an mRNA 3? processing factor. We hypothesize that the binding of CstF-50 to both BRCA1/BARD1 and its substrates helps in the assembly and/or stabilization of the ubiquitination complex during DDR, resulting in the functional regulation of chromatin structure and gene expression. To further explore this novel phenomenon we propose to determine the molecular mechanism(s) involved in CstF-50? mediated regulation BRCA1/BARD1 Ub ligase activity; and to analyze the effect of CstF- 50/BRCA1/BARD1 ubiquitination complex on chromatin structure/gene expression during DDR. These aims will be tested by using a combination of biochemical, molecular and cell biology approaches. The physiological relevance of the BRCA1/BARD1 ubiquitination pathway is not well understood. The successful completion of this project will give new insights into the mechanisms involved in DDR and lead to fundamental understanding of the role of an RNA processing factor in the context of the Ub pathway and chromatin. Knowledge gained will help us to understand the way in which cells respond to DNA damage, affecting cell death or survival, mutation rates, aging and cancer. This grant will provide research support to a PI from a minority serving institution that is in the unique position of being a woman scientist originally from Latin America.

R21CA204610

2017-03-08

2020-02-29