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dc.contributor.authorNakas, Apostolos
dc.contributor.authorDawson, Alan
dc.contributor.authorFennell, Dean
dc.date.accessioned2023-06-02T15:10:11Z
dc.date.available2023-06-02T15:10:11Z
dc.date.issued2022-12-22
dc.identifier.citationSingh, A., Busacca, S., Gaba, A., Sheaff, M., Poile, C., Nakas, A., Dzialo, J., Bzura, A., Dawson, A. G., Fennell, D. A., & Fry, A. M. (2023). BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms. Oncogene, 42(8), 572–585. https://doi.org/10.1038/s41388-022-02577-3en_US
dc.identifier.other10.1038/s41388-022-02577-3
dc.identifier.urihttp://hdl.handle.net/20.500.12904/17134
dc.description.abstractThe 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.
dc.description.urihttps://www.nature.com/articles/s41388-022-02577-3en_US
dc.language.isoenen_US
dc.titleBAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanismsen_US
dc.typeArticleen_US
rioxxterms.funderDefault funderen_US
rioxxterms.identifier.projectDefault projecten_US
rioxxterms.versionNAen_US
rioxxterms.versionofrecordhttps://doi.org/10.1038/s41388-022-02577-3en_US
rioxxterms.typeJournal Article/Reviewen_US
refterms.panelUnspecifieden_US
html.description.abstractThe 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.en_US
rioxxterms.funder.project94a427429a5bcfef7dd04c33360d80cden_US


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