Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response

Caveolae-associated protein 3 (cavin3), a putative tumor suppressor protein, is inactivated in most cancers. The molecular basis for its actions remains poorly understood. We characterized the effects on the proteome of cavin3 loss by utilizing genome-edited cells together with label-free quantitative proteomics. These studies revealed a prominent role for cavin3 in DNA repair pathways with downregulation of BRCA1 and the BRCA1 A-complex components. Using cellular and cell-free expression assays, we show a direct interaction between BRCA1 and cavin3. Association of BRCA1 and cavin3 occurs when cavin3 is released from disassembling caveolae by multiple stressors such as UV and mechanical stress. Cavin3-deficient cells were sensitised to PARP inhibition and showed a loss of components of the BRCA1 A-complex associated with UV DNA damage foci. Overexpression and RNAi-depletion strategies in several cancer cell lines revealed that cavin3 sensitized a variety of cancer cells to UV-induced apoptosis. We conclude that cavin3 functions together with BRCA1 in multiple pathways that contribute to tumorigenesis.