Cavin3 released from caveolae interacts with BRCA1to regulate the cellular stress response

Parton, R. G.; McMahon, K.-A.; Stroud, D. A.; Gambin, Y.; Tillu, V.; Bastiani, M.; Sierecki, E.; Polinkovsky, M.; Hall, T. E.; Gomez, G. A.; Wu, Y.; Parat, M.-O.; Martel, N.; Lo, H. P.; Khanna, K. k.; Alexandrov, K.; Daly, R.; Yap, A. S.; Ryan, M.

doi:10.1101/2020.07.26.222158

bioRxiv · 10.1101/2020.07.26.222158

Cavin3 released from caveolae interacts with BRCA1to regulate the cellular stress response

Parton, R. G.·McMahon, K.-A.·Stroud, D. A.·Gambin, Y.·Tillu, V.·Bastiani, M.·Sierecki, E.·Polinkovsky, M.·Hall, T. E.·Gomez, G. A.·Wu, Y.·Parat, M.-O.·Martel, N.·Lo, H. P.·Khanna, K. k.·Alexandrov, K.·Daly, R.·Yap, A. S.·Ryan, M.

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Abstract

Caveolae-associated protein 3 (cavin3), a putative tumor suppressor protein, 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, we show a direct interaction between BRCA1 and cavin3. Association of BRCA1 and cavin3 occurs when cavin3 is released from caveolae that are disassembled in response to UV and mechanical stress. Supporting a role in DNA repair, cavin3-deficient cells were sensitized to the effects of PARP inhibition, which compromises DNA repair, and showed reduced recruitment of the BRCA1 A-complex to UV DNA damage foci. Overexpression and RNAi-depletion revealed that cavin3 sensitized various cancer cells to UV-induced apoptosis. We conclude that cavin3 functions together with BRCA1 in multiple pathways that contribute to tumorigenesis.

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Parton, R. G., McMahon, K.-A., Stroud, D. A., Gambin, Y., Tillu, V., Bastiani, M., Sierecki, E., Polinkovsky, M., Hall, T. E., Gomez, G. A., Wu, Y., Parat, M.-O., Martel, N., Lo, H. P., Khanna, K. k., Alexandrov, K., Daly, R., Yap, A. S., Ryan, M.. 2020-07-26. Cavin3 released from caveolae interacts with BRCA1to regulate the cellular stress response. https://doi.org/10.1101/2020.07.26.222158

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