Genome-wide RNAi to identify genes that confer synthetic lethality with BRCA1

We have previously demonstrated that a functional orthologue of the breast cancer tumour suppressor gene BRCA1 exists in C. elegans (brc-1). Deletion mutants in C. elegans brc-1 or its heterodimeric partner, brd-1, share many of the phenotypic hallmarks of BRCA1-deficient human cells, yet are homozygous viable thus permitting extensive reverse genetic analysis. Using a rapid and inexpensive genome-wide screen in C. elegans we set out to identify genes that could be targeted in human patients to selectively kill tumours defective in the BRCA pathway. To this end we have utilized the complete C. elegans RNA-mediated interference library to systematically inactivate all 19,500 C. elegans genes and have identified those genes whose depletion confers synthetic lethality in combination with brc-1 and brd-1 mutations. In total, this screen identified 20 genes including pme-1 and pme-2, the C. elegans counterparts of PARP, a gene whose inhibition selectively kills BRCA defective tumour cells. We are currently using siRNA to knockdown all human homologues to identify those genes whose inactivation specifically kills mammalian cells harbouring mutations in BRCA1. These results and our current progress will be presented.