Sir William Dunn School of Pathology,
University of Oxford

Fumiko Esashi

Germline mutations in genes encoding the breast cancer 2 (BRCA2) and the partner and localizer of BRCA2 (PALB2) significantly increase the risk of human diseases such as Fanconi anaemia (FA). Paradoxically, however, BRCA2 and PALB2 are essential for the survival of non-cancerous cells, in part because of their well-documented roles in facilitating DNA repair and replication. Remarkably, BRCA2- or PALB2-deficient cancers display a wide range of mutations and genomic instability, and thus the development of drug resistance is common and poses serious clinical problems. We aim to address this problem by conducting unbiased genome-wide double screens using CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) in cell lines capable of long-term conditional depletion of BRCA2 or PALB2. This collaborative project will allow us to identify factors that affect the survival of cells lacking BRCA2 or PALB2, with reduced impact of stochastic secondary mutations that are common in widely used BRCA1/2 knockout cancer cell lines. This study also provides insight into the poorly understood function of PALB2, a factor that bridges BRCA1 and BRCA2 in the error-free repair of DNA breaks by homologous recombination.