A novel role of BAP1 in regulating the spindle assembly checkpoint and mitotic spindle assembly


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Anita Singh1,Dean Fennell1,Andrew Fry1
1University of Leicester, Leicester, UK

Abstract

Background

BRCA1 associated protein 1 (BAP1) is a tumour suppressor that plays critical roles in cell cycle regulation, transcription, cell death and DNA damage repair. Germline or somatic mutations and copy number alterations have been identified in several cancers and inactivation of BAP1 accelerates invasion, recurrence and metastases. BAP1 loss can modulate the response to chemotherapeutic drugs. However it is unknown how BAP1 status modulates the response to the DNA damaging agents or anti-microtubule drugs. The aim of this study was to identify how BAP1 regulates the DNA repair, SAC and mitosis.

Method

Functional genetic analysis of SAC proteins was conducted after BAP1 depletion using siRNA transfection. Spindle length and aster volume as measured in Imaris3D. Stable cell lines with wildtype or mutants of BAP1 were irradiated to induce DNA damage.

Results

Loss of BAP1 led to mitotic spindle defects such as elongated spindle length, increased aster volume by regulating the localization and expression of motor proteins, KIF18A and KIF18B. BAP1 is required to maintain SAC integrity through stimulating MAD2 expression and BUBR1 recruitment to kinetochores. Expression of wild type and mutants of BAP1 increased BRCA1 foci after DNA damage.

Conclusion

The findings suggest a novel role for BAP1 in regulating mitotic spindle assembly and regulating genomic stability. Our findings also suggest that during DNA damage BAP1 is required to recruit BRCA1 foci for DNA repair. Our results also suggest that the association between BAP1 and SAC may be clinically relevant. Vinorelbine exhibits useful clinical activity in mesothelioma and is currently being evaluated in a multicentre randomised phase II trial (VIM, NCT02139904) and patients are currently screened for BAP1 status for MIST trial. BAP1 has the potential as a predictive biomarker for chemotherapeutic drugs, to underpin chemotherapy stratification.