Molecular mechanisms of BRCA1/2-mediated genome stability maintenance

The National Institute of General Medical Sciences, part of the Department of Health and Human Services National Institutes of Health, awarded the University of Texas Health Science Center at San Antonio $433,976 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate molecular mechanisms of BRCA1/2-mediated genome stability maintenance.

The funded research addresses homologous recombination pathways and DNA double-strand break repair in mammalian cells. The project will identify and characterize chromatin-interacting modules in BRCA1-BARD1 complexes required for chromatin recruitment and DNA strand invasion; determine how BRCA1-BARD1 E3 ligase activity regulates DNA end resection through ubiquitylation of inhibitory and stimulatory factors; and elucidate how DSS1 modulates BRCA2 conformation to restrict nonspecific double-strand DNA binding and facilitate RAD51 loading onto single-strand DNA. The work will employ biochemical and structural dissection of purified BRCA1-BARD1 and BRCA2-DSS1 complexes developed in the recipient's laboratory.

Performance occurs in San Antonio, Texas, with a period of performance extending from September 1, 2026, through May 31, 2031. The assistance type is a Project Grant.

Abstract

Homologous recombination (HR) is a conserved and essential pathway for repairing DNA double-strand breaks and maintaining genome integrity. While HR mechanisms are well characterized in bacteria and yeast, our understanding in mammals remains incomplete due to the complexity of mammalian systems and the presence of unique regulatory factors. Key tumor suppressors-including BRCA1 and BRCA2-are essential HR components in humans, but mechanistic studies have been hindered by the difficulty of producing these large, multidomain proteins and complexes. My laboratory has developed robust systems for expressing and purifying BRCA1-BARD1 and BRCA2-DSS1, enabling a new level of biochemical and structural dissection. This proposal aims to define how BRCA1-BARD1 and BRCA2-DSS1 coordinate distinct but interdependent steps in HR. Specifically, we will (1) identify and functionally characterize chromatin-interacting modules in BRCA1-BARD1 required for chromatin recruitment and DNA strand invasion; (2) determine how BRCA1-BARD1 E3 ligase activity regulates DNA end resection through ubiquitylation of both inhibitory (e.g., CST) and stimulatory (e.g., ctip) factors; and (3) elucidate how DSS1 modulates BRCA2 conformation to restrict nonspecific dsdna binding and facilitate RAD51 loading onto ssdna. Together, these studies will uncover how multivalent interactions and post- translational regulation orchestrate BRCA1/2 mediated HR in mammalian cells. The work will provide fundamental insight into genome maintenance mechanisms, supporting the nigms mission to understand basic cellular processes that underlie human health.