Our cells are constantly exposed to endogenous and exogenous causes of DNA damage, such as DNA-damaging chemicals, irradiation and replication errors. Luckily, cells are equipped with efficient mechanisms to repair such damage to maintain genomic integrity. BRCA1 is a key protein for the repair of DNA double-stranded breaks via homologous recombination (HR). BRCA1 mutations occur in a wide variety of tumors, including hereditary forms of breast and ovarian cancer, but also lung and gastric cancer. BRCA1-mutated tumors are characterised by gross chromosomal instability. However, how all the different mutations in BRCA1 are involved in cancer development and therapy response is often still unclear.
One of the main complexities in studying BRCA1 function is the fact that it forms several multi-protein complexes via its different protein domains. Most of these complexes stimulate HR, but others - counter intuitively - inhibit HR. The main question in my lab is to better understand how all these different BRCA1-complexes cooperate to maintain genomic stability and how mutations disrupting single complexes affect tumorigenesis. My lab uses a combination of systematic approaches, such as genome-wide CRISPR-Cas9 screens and proteomics, and dedicated functional assays in mammalian cell systems to study the mechanisms of BRCA1 function.