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.Description of research projects
- Johnson N, Speirs V, Curtin NJ and Hall AG. A comparative study of genome-wide SNP, CGH microarray and protein expression analysis to explore genotypic and phenotypic mechanisms of acquired antiestrogen resistance in breast cancer. Breast Cancer Res Treat 2008 Sep;111(1):55-63.
- Johnson N, Cai D, Kennedy RD, Pathania S, Arora M, Li YC, D'Andrea AD, Parvin J.D and Shapiro GI. CDK1 participates in BRCA1-dependent S phase checkpont control in response to DNA damage. Molecular Cell 2009 Aug 14;35(3):327-39.
- Johnson N, Bentley J, Wang LZ, Newell DR, Robson CN, Shapiro GI, Curtin NJ. Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen sensitive and resistant breast cancer cells. Br J Cancer 2010 Jan 19;102(2):342-50.
- Johnson N, Li Y-C, Walton ZE, Cheng KA, Li D, Rodig SJ, Moreau LA, Unitt C, Bronson RT, Thomas HD, Newell DR, D'Andrea AD, Curtin NJ, Wong KK, Shapiro GI. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nature Medicine 2011 Jun 26;17(7):875-82.
- Johnson N, Johnson SF, Yao W, Bernhardy AB, Wang Y, Li Y-L, Choi Y-E, Capelletti M, Sarosiek KA, Moreau LA, Chowdhury D, Wickramanayake A, Harrell M, Liu JF, D'Andrea AD, Miron A, Swisher EM, Shapiro GI. Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance. PNAS. In press.