RAD51 paralog function in cancer predisposition and genome integrity

Project Summary/Abstract:
Accurate repair of DNA damage is critical for genetic stability, and for preventing aging-related degeneration
and cancer. We are working to identify key factors that regulate accurate repair of DNA double-strand breaks
(DSBs) through the error-free homologous recombination (HR) pathway. DSBs can arise from many sources
including endogenous replication fork damage, exogenous environmental toxicants, or oxidative stresses
induced by endogenous sources and during pro-inflammatory responses to toxicant injury. We found that the
RAD51 paralogs are critical for promoting HR and hence for suppressing error-prone repair mechanisms. Over
300 studies link mutations in human RAD51 paralogs with cancer, and women with breast or ovarian cancer
are now screened for RAD51 paralog mutations. However, it remains largely unknown which RAD51 paralog
mutations are pathogenic and how these mutations sensitize individuals to environmentally induced-DNA
damage due to our lack of functional analysis of either the wild-type or mutated proteins. We do not know how
these proteins are recruited, their functional components, or the disruptions caused by mutations or
polymorphisms in the RAD51 paralogs. This knowledge gap results from low abundance of endogenous
RAD51 paralog proteins, insolubility of the recombinant proteins, as well as embryonic lethality in knock-out
mice. We are therefore using genetic, biochemical, and cell biological approaches to characterize RAD51
paralog function upon exposure to DSB inducing agents. We will use ionizing radiation (IR) and bleomycin as
model agents for environmentally relevant DSB-inducing agents. Using complementary approaches in
combination with high-throughput genetic screening, we are now uniquely poised to address how RAD51
paralog mutations predispose individuals to human cancer and thus, to identify opportunities for determining
who is at risk for cancer development upon exposure to environmental carcinogens. Our ultimate goal is to
enable development of precision medicine strategies for individual patients whose tumors harbor a RAD51
paralog mutation profile.

Grant Number: 5R01ES031796-05
NIH Institute/Center: NIH
Principal Investigator: Kara Bernstein