TY - JOUR TI - Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response AU - McMahon, Kerrie-Ann AU - Stroud, David A AU - Gambin, Yann AU - Tillu, Vikas AU - Bastiani, Michele AU - Sierecki, Emma AU - Polinkovsky, Mark E AU - Hall, Thomas E AU - Gomez, Guillermo A AU - Wu, Yeping AU - Parat, Marie-Odile AU - Martel, Nick AU - Lo, Harriet P AU - Khanna, Kum Kum AU - Alexandrov, Kirill AU - Daly, Roger AU - Yap, Alpha AU - Ryan, Michael T AU - Parton, Robert G A2 - Schlacher, Katharina A2 - Tyler, Jessica K A2 - Liu, Libin VL - 10 PY - 2021 DA - 2021/06/18 SP - e61407 C1 - eLife 2021;10:e61407 DO - 10.7554/eLife.61407 UR - https://doi.org/10.7554/eLife.61407 AB - 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. KW - BRCA1 KW - breast cancer KW - caveolae KW - cavin proteins JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -