Sharon Cantor Receives NIH Grant to Investigate New Role for BRCA1

Sharon Cantor, PhD, has received an R01 grant from the National Cancer Institute to investigate a newly emerging role for BRCA1, a tumor suppressor gene frequently mutated in hereditary breast and ovarian cancers.

BRCA1 has long been known for its role in homologous recombination, and the prevailing view has been that BRCA1-deficient cells have defects in double-strand break repair that underlie their sensitivity to genotoxic anti-cancer agents such as PARP inhibitors and cisplatin, which are thought to kill cells by inducing double-strand breaks.

Research from the Cantor Lab is challenging this model. Over the past several years, the lab has shown that BRCA1 also plays a critical role in suppressing single-stranded DNA replication-associated gaps, and that BRCA1-deficient cells accumulate these lesions. The lab has further shown that PARP inhibitors exacerbate replication-associated gaps, supporting a model in which these single-strand gaps, rather than double-strand breaks, underlie the sensitivity of BRCA1-deficient cancers to therapy. More recently, the team found that replication-associated gaps create a dependency on the DNA repair protein RAD51 to protect these sites.

The new project will investigate how BRCA1 prevents the formation of these gaps. Cantor and her team hypothesize that BRCA1 coordinates lagging strand synthesis and that disruption of this process leads to gap formation and downstream RAD51 dependence. The project aims to define the role of BRCA1 in lagging strand synthesis, determine how defects in lagging strand processing are bypassed in BRCA1-deficient cells, and uncover how RAD51 protects and resolves the gaps.

By defining BRCA1’s role in lagging strand DNA replication, the work may reveal new mechanisms underlying therapeutic sensitivity in BRCA1-deficient cancers and identify new strategies for targeting tumors that are resistant to PARP inhibitors.