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

Kerrie Ann McMahon, David A. Stroud, Yann Gambin, Vikas A. Tillu, Michele Bastiani, Emma Sierecki, Mark Polinkovsky, Thomas E. Hall, Guillermo A. Gomez, Yeping Wu, Marie Odile Parat, Nick Martel, Harriet P. Lo, Kum Kum Khanna, Kirill Alexandrov, Roger Daly, Alpha S. Yap, Michael T. Ryan, Robert G. Parton

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

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. 

Original languageEnglish
Article numbere61407
Number of pages35
JournaleLife
Volume10
DOIs
Publication statusPublished - Jun 2021

Keywords

  • BRCA1
  • Breast cancer
  • Caveolae
  • Cavin proteins

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