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BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms.

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posted on 2023-07-25, 15:31 authored by Anita Singh, Sara Busacca, Aarti Gaba, Michael Sheaff, Charlotte Poile, Apostolos Nakas, Joanna Dzialo, Aleksandra Bzura, Alan G Dawson, Dean A Fennell, Andrew M Fry
The tumour suppressor BRCA1-associated protein 1 (BAP1) is the most frequently mutated cancer gene in mesothelioma. Here we report novel functions for BAP1 in mitotic progression highlighting the relationship between BAP1 and control of genome stability in mesothelioma cells with therapeutic implications. Depletion of BAP1 protein induced proteasome-mediated degradation of BRCA1 in mesothelioma cells while loss of BAP1 correlated with BRCA1 loss in mesothelioma patient tumour samples. BAP1 loss also led to mitotic defects that phenocopied the loss of BRCA1 including spindle assembly checkpoint failure, centrosome amplification and chromosome segregation errors. However, loss of BAP1 also led to additional mitotic changes that were not observed upon BRCA1 loss, including an increase in spindle length and enhanced growth of astral microtubules. Intriguingly, these consequences could be explained by loss of expression of the KIF18A and KIF18B kinesin motors that occurred upon depletion of BAP1 but not BRCA1, as spindle and astral microtubule defects were rescued by re-expression of KIF18A and KIF18B, respectively. We therefore propose that BAP1 inactivation causes mitotic defects through BRCA1-dependent and independent mechanisms revealing novel routes by which mesothelioma cells lacking BAP1 may acquire genome instability and exhibit altered responses to microtubule-targeted agents.

Funding

This work was supported by grants to A.M.F. from Worldwide Cancer Research (formerly Association for International Cancer Research; 13-0042 and 16-0119), the Wellcome Trust (082828 and 097828) and Cancer Research UK (C1362/A180081).

History

Citation

Singh, A., Busacca, S., Gaba, A. et al. BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms. Oncogene 42, 572–585 (2023). https://doi.org/10.1038/s41388-022-02577-3

Author affiliation

Department of Molecular and Cell Biology

Version

  • VoR (Version of Record)

Published in

Oncogene

Volume

42

Pagination

572–585

Publisher

Springer Science and Business Media LLC

issn

0950-9232

eissn

1476-5594

Acceptance date

2022-12-09

Copyright date

2022

Available date

2023-07-25

Spatial coverage

England

Language

eng

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