Mutations in BRCA1 and BRCA2 genes confer high lifetime risks of developing breast and other cancers. Moreover, several studies suggest that tumours arising in mutation carriers have generally lost the wild-type allele and do not express functional BRCA1 or BRCA2 proteins. Both BRCA proteins are important for repair of double strand DNA breaks by homologous recombination. The subject of this project would allow us to clarify if cells harbouring defects in DNA damage repair (such as BRCA1 deficient cells) are more sensitive to the induced loss of other DNA repair mechanisms (either by RNAi or small molecule inhibitors). For that purpose I will perform High-throughput RNA interference screenings to find synthetic lethality partners for BRCA1 and BRCA2, using a library of siRNAs targeting 779 proteins that encompass all the known and predicted kinases. I will also translate some previous yeast synthetic lethality studies, to human breast cancer cell lines, performing for that a”mini-RNAi screen”. Ultimately, this project presented here may lead to the identification of novel anticancer strategies targeting DNA repair defects in tumors, which could be applicable in several sporadic cancers.
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