Abstract

Caveolae-associated protein 3 (cavin3) is inactivated in most cancers. We characterized how cavin3 affects the cellular proteome using genome-edited cells together with label-free quantitative proteomics. These studies revealed a prominent role for cavin3 in DNA repair, with BRCA1 and BRCA1 A-complex components being downregulated on cavin3 deletion. Cellular and cell-free expression assays revealed a direct interaction between BRCA1 and cavin3 that occurs when cavin3 is released from caveolae that are disassembled in response to UV and mechanical stress. Overexpression and RNAi-depletion revealed that cavin3 sensitized various cancer cells to UV-induced apoptosis. Supporting a role in DNA repair, cavin3-deficient cells were sensitive to PARP inhibition, where concomitant depletion of 53BP1 restored BRCA1-dependent sensitivity to PARP inhibition. We conclude that cavin3 functions together with BRCA1 in multiple cancer-related pathways. The loss of cavin3 function may provide tumor cell survival by attenuating apoptotic sensitivity and hindering DNA repair under chronic stress conditions.

Authors	McMahon, Kerrie-Ann; Stroud, David A; Gambin, Yann; Tillu, Vikas; Bastiani, Michele; Sierecki, Emma; Polinkovsky, Mark E; Hall, Thomas E; Gomez, Guillermo A; Wu, Yeping; Parat, Marie-Odile; Martel, Nick; Lo, Harriet P; Khanna, Kum Kum; Alexandrov, Kirill; Daly, Roger; Yap, Alpha; Ryan, Michael T; Parton, Robert G
Journal	Elife
Pages
Volume	10
Date	1/01/2021
Grant ID
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.7554/eLife.61407