Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response
- Institute for Molecular Bioscience, University of Queensland, Australia
- The University of Melbourne, Australia
- University of New South Wales, Australia
- University of Queensland, Australia
- The University of Queensland, Australia
- Institute for Molecular Bioscience, Australia
- HMRI, United States
- Monash University, Australia
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.
Data availability
All reagents are available from the corresponding author upon request. Proteomics data that supports the findings of this study is presented in Supplementary File 1 and 2. Raw western blots with molecular weight markers are presented in source data files.The raw mass spectrometry proteomics data for this manuscript comparing HeLa WT and HeLa cavin3 KO cells has been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD026724.
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Funding
National Health and Medical Research Council (APP1140064)
- Robert G Parton
National Health and Medical Research Council (APP1150083)
- Robert G Parton
National Health and Medical Research Council (APP1156489)
- Robert G Parton
National Health and Medical Research Council (APP1037320)
- Robert G Parton
National Health and Medical Research Council (APP1044041)
- Alpha Yap
National Health and Medical Research Council (APP1125390)
- Michael T Ryan
National Health and Medical Research Council (APP1070916)
- David A Stroud
National Health and Medical Research Council (APP1140851)
- David A Stroud
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, McMahon et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response
eLife 10:e61407.
https://doi.org/10.7554/eLife.61407
