Neil Johnson, PhD
Member & Assistant Professor
Office Phone: 215-728-7016
BRCA1 Gene and BRCA Mutations
The BRCA1 gene is commonly mutated in hereditary breast and ovarian cancers. Mutations occur most frequently in the N-terminal RING, exons 11-13, or the BRCA C-terminal (BRCT) domain. The BRCA1 protein has multiple domains that mediate protein interactions; BRCA1 gene mutations may produce truncated proteins that lose the ability to interact with associated proteins. Additionally, mutations in the BRCT domain of BRCA1 create protein-folding defects that result in protease-mediated degradation. Cells that contain dysfunctional BRCA1 proteins are hypersensitive to DNA damaging agents. In particular, BRCA1-deficient cell lines are exquisitely sensitive to poly(ADP- ribose) polymerase (PARP) inhibitor treatment. Despite substantial response rates of BRCA1 mutant cancers to PARP inhibitor treatment, many patients harboring BRCA1 mutant tumors fail to respond to treatment; additionally, patients that demonstrate initial responses ultimately acquire drug resistant tumors.
Our research involves investigating factors that enable cancer cells containing BRCA mutations to carry out homologous recombination DNA repair and survive DNA damaging agent chemotherapy. Several factors may contribute to homologous recombination DNA repair proficiency in BRCA mutant tumors. We are examining the ability of mutant BRCA1 proteins to contribute to homologous recombination in cancer cells. Additionally, in collaboration with the Broad Institute at MIT/Harvard, we have screened a genome scale open reading frame (ORF) library to identify proteins that provide PARP inhibitor resistance. Furthermore, we are measuring the ability of novel or established compounds in preclinical or clinical development to abrogate DNA repair pathways. Our overarching goal is to exploit discoveries in basic science for therapeutic benefit and translation to clinical trials.Top