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

doi:10.7554/eLife.61407

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 journal › Article › Research › peer-review

17 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 language	English
Article number	e61407
Number of pages	35
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.61407
Publication status	Published - Jun 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

BRCA1
Breast cancer
Caveolae
Cavin proteins

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10.7554/eLife.61407Licence: CC BY

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McMahon, K. A., Stroud, D. A., Gambin, Y., Tillu, V. A., 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. T., & Parton, R. G. (2021). Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response. eLife, 10, Article e61407. https://doi.org/10.7554/eLife.61407

@article{817098ce2b10418aac83d69870c6e635,

title = "Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response",

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. ",

keywords = "BRCA1, Breast cancer, Caveolae, Cavin proteins",

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

note = "Funding Information: We would like to thank Markus Kerr, Nicholas Ariotti, Aaron Smith and Brian Gabrielli for valuable discussion. This work was supported by fellowships and grants from the National Health and Medical Research Council of Australia (to R.G. Parton, (grants APP1140064 and APP1150083 and fellowship APP1156489), R.G. Parton and A.S. Yap, grant number APP1037320, to A.S. Yap, grant number APP1044041, to M.T. Ryan and D.A. Stroud, grant number APP1125390, to D.A. Stroud, grant numbers APP1070916 and APP1140851) as well as by the Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (R.G. Parton) and the Kids Cancer Project of the Oncology Research Foundation (A.S. Yap). Confocal microscopy was performed at the Australian Cancer Research Foundation (ACRF)/Institute for Molecular Bioscience (IMB) Dynamic Imaging Facility for Cancer Biology, established with funding from the ACRF. The authors acknowledge the use of the Monash Biomedical Proteomics Facility for the provision of instrumentation, training, and technical support. We also thank Beric Henderson (Westmead Institute for Cancer Research, University of Sydney, Australia) for the BRCA1-YFP construct. Publisher Copyright: {\textcopyright} 2021, eLife Sciences Publications Ltd. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jun,

doi = "10.7554/eLife.61407",

language = "English",

volume = "10",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Organisation, Ltd.",

}

McMahon, KA, Stroud, DA, Gambin, Y, Tillu, VA, Bastiani, M, Sierecki, E, Polinkovsky, M, Hall, TE, Gomez, GA, Wu, Y, Parat, MO, Martel, N, Lo, HP, Khanna, KK, Alexandrov, K, Daly, R, Yap, AS, Ryan, MT & Parton, RG 2021, 'Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response', eLife, vol. 10, e61407. https://doi.org/10.7554/eLife.61407

TY - JOUR

T1 - 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 A.

AU - Bastiani, Michele

AU - Sierecki, Emma

AU - Polinkovsky, Mark

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 S.

AU - Ryan, Michael T.

AU - Parton, Robert G.

N1 - Funding Information: We would like to thank Markus Kerr, Nicholas Ariotti, Aaron Smith and Brian Gabrielli for valuable discussion. This work was supported by fellowships and grants from the National Health and Medical Research Council of Australia (to R.G. Parton, (grants APP1140064 and APP1150083 and fellowship APP1156489), R.G. Parton and A.S. Yap, grant number APP1037320, to A.S. Yap, grant number APP1044041, to M.T. Ryan and D.A. Stroud, grant number APP1125390, to D.A. Stroud, grant numbers APP1070916 and APP1140851) as well as by the Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (R.G. Parton) and the Kids Cancer Project of the Oncology Research Foundation (A.S. Yap). Confocal microscopy was performed at the Australian Cancer Research Foundation (ACRF)/Institute for Molecular Bioscience (IMB) Dynamic Imaging Facility for Cancer Biology, established with funding from the ACRF. The authors acknowledge the use of the Monash Biomedical Proteomics Facility for the provision of instrumentation, training, and technical support. We also thank Beric Henderson (Westmead Institute for Cancer Research, University of Sydney, Australia) for the BRCA1-YFP construct. Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/6

Y1 - 2021/6

N2 - 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.

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

UR - https://www.scopus.com/pages/publications/85109022484

U2 - 10.7554/eLife.61407

DO - 10.7554/eLife.61407

M3 - Article

C2 - 34142659

AN - SCOPUS:85109022484

SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

M1 - e61407

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Translating membrane proteins into therapeutics; from bedside to bench

Systems approaches to understanding mitochondrial function and dysfunction in disease

Assembly and misassembly of mitochondrial respiratory chain Complex I

Cite this

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

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Projects

Translating membrane proteins into therapeutics; from bedside to bench

Systems approaches to understanding mitochondrial function and dysfunction in disease

Assembly and misassembly of mitochondrial respiratory chain Complex I

Cite this