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

  1. Kerrie-Ann McMahon
  2. David A Stroud
  3. Yann Gambin
  4. Vikas Tillu
  5. Michele Bastiani
  6. Emma Sierecki
  7. Mark E Polinkovsky
  8. Thomas E Hall
  9. Guillermo A Gomez
  10. Yeping Wu
  11. Marie-Odile Parat
  12. Nick Martel
  13. Harriet P Lo
  14. Kum Kum Khanna
  15. Kirill Alexandrov
  16. Roger Daly
  17. Alpha Yap
  18. Michael T Ryan
  19. Robert G Parton  Is a corresponding author
  1. Institute for Molecular Bioscience, University of Queensland, Australia
  2. The University of Melbourne, Australia
  3. University of New South Wales, Australia
  4. University of Queensland, Australia
  5. The University of Queensland, Australia
  6. Institute for Molecular Bioscience, Australia
  7. HMRI, United States
  8. 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.

The following data sets were generated

Article and author information

Author details

  1. Kerrie-Ann McMahon

    Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. David A Stroud

    Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Yann Gambin

    EMBL Australia Node in Single Molecule Sciences, University of New South Wales, sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7378-8976
  4. Vikas Tillu

    Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1034-9543
  5. Michele Bastiani

    Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Emma Sierecki

    EMBL Australia Node in Single Molecule Sciences, University of New South Wales, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Mark E Polinkovsky

    Institute for Molecular Bioscience, University of Queensland, Brsbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Thomas E Hall

    Cell Biology and Molecular Medicine, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7718-7614
  9. Guillermo A Gomez

    Department of Cell and Developmental Biology, Institute for Molecular Bioscience, St. Lucia, Brisbane, Queensland, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Yeping Wu

    Cell Biology and Molecular Medicine, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Marie-Odile Parat

    School of Pharmacy, University of Queensland, Queensland, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Nick Martel

    Cell Biology and Molecular Medicine, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. Harriet P Lo

    Department of Cell and Developmental Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  14. Kum Kum Khanna

    Radiation Oncology, HMRI, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Kirill Alexandrov

    Department of Cell and Developmental Biology, Institute for Molecular Bioscience, St. Lucia, Brisbane, Queensland, Australia
    Competing interests
    The authors declare that no competing interests exist.
  16. Roger Daly

    Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5739-8027
  17. Alpha Yap

    School of Pharmacy, University of Queensland, Queensland, Australia
    Competing interests
    The authors declare that no competing interests exist.
  18. Michael T Ryan

    Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  19. Robert G Parton

    Cell Biology and Molecular Medicine, University of Queensland, Brisbane, Australia
    For correspondence
    r.parton@imb.uq.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7494-5248

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.

Reviewing Editor

  1. Katharina Schlacher, UT MD Anderson Cancer Center, United States

Version history

  1. Received: July 24, 2020
  2. Accepted: June 11, 2021
  3. Accepted Manuscript published: June 18, 2021 (version 1)
  4. Version of Record published: July 14, 2021 (version 2)

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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  1. Kerrie-Ann McMahon
  2. David A Stroud
  3. Yann Gambin
  4. Vikas Tillu
  5. Michele Bastiani
  6. Emma Sierecki
  7. Mark E Polinkovsky
  8. Thomas E Hall
  9. Guillermo A Gomez
  10. Yeping Wu
  11. Marie-Odile Parat
  12. Nick Martel
  13. Harriet P Lo
  14. Kum Kum Khanna
  15. Kirill Alexandrov
  16. Roger Daly
  17. Alpha Yap
  18. Michael T Ryan
  19. Robert G Parton
(2021)
Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response
eLife 10:e61407.
https://doi.org/10.7554/eLife.61407

Share this article

https://doi.org/10.7554/eLife.61407

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