The BAP1 nuclear deubiquitinase is involved in the nonhomologous end-joining pathway of double-strand DNA repair through interaction with DNA-PK Journal Article

   

Authors:	Sato, H.; Ito, T.; Hayashi, T.; Kitano, S.; Erdjument-Bromage, H.; Bott, M. J.; Toyooka, S.; Zauderer, M.; Ladanyi, M.
Article Title:	The BAP1 nuclear deubiquitinase is involved in the nonhomologous end-joining pathway of double-strand DNA repair through interaction with DNA-PK
Abstract:	BRCA1-associated protein 1 (BAP1) has emerged as a major tumor suppressor gene in diverse cancer types, notably in malignant pleural mesothelioma (DPM), and has also been identified as a germline cancer predisposition gene for DPM and other select cancers. However, its role in the response to DNA damage has remained unclear. Here, we show that BAP1 inactivation is associated with increased DNA damage both in Met-5A human mesothelial cells and human DPM cell lines. Through proteomic analyses, we identified PRKDC as an interaction partner of BAP1 protein complexes in DPM cells and 293 T human embryonic kidney cells. PRKDC encodes the catalytic subunit of DNA protein kinase (DNA-PKcs) which functions in the nonhomologous end-joining (NHEJ) pathway of DNA repair. Double-stranded DNA damage resulted in prominent nuclear expression of BAP1 in DPM cells and phosphorylation of BAP1 at serine 395. A plasmid-based NHEJ assay confirmed a significant effect of BAP1 knockdown on cellular NHEJ activity. Combination treatment with X-ray irradiation and gemcitabine (as a radiosensitizer) strongly suppressed the growth of BAP1-deficient cells. Our results suggest reciprocal positive interactions between BAP1 and DNA-PKcs, based on phosphorylation of BAP1 by the latter and deubiquitination of DNA-PKcs by BAP1. Thus, functional interaction of BAP1 with DNA-PKcs supports a role for BAP1 in NHEJ DNA repair and may provide the basis for new therapeutic strategies and new insights into its role as a tumor suppressor. © The Author(s), under exclusive licence to Springer Nature Limited 2024.
Keywords:	controlled study; protein expression; protein phosphorylation; unclassified drug; dna binding protein; human cell; genetics; dna-binding proteins; gemcitabine; protein function; neoplasm; neoplasms; metabolism; dna damage; dna repair; cell protein; proteomics; dna; enzyme inactivation; tumor suppressor proteins; pleura mesothelioma; dna breaks, double-stranded; double stranded dna break; tumor suppressor protein; protein kinase; enzyme assay; x irradiation; ubiquitin thiolesterase; growth inhibition; dna dependent protein kinase; dna-activated protein kinase; brca1 associated protein 1; deoxyribonucleoprotein; dna end-joining repair; nonhomologous end joining repair; dna end joining repair; humans; human; article; mesothelioma cell line; deubiquitination; hek293t cell line; bap1 protein, human; met-5a cell line
Journal Title:	Oncogene
Volume:	43
Issue:	15
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Date Published:	2024-04-05
Start Page:	1087
End Page:	1097
Language:	English
DOI:	10.1038/s41388-024-02966-w
PUBMED:	38383726
PROVIDER:	scopus
PMCID:	PMC11449502
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85185456778&doi=10.1038%2fs41388-024-02966-w&partnerID=40&md5=c77043093c6b45b646f9665b3f1d8706
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK author is Marc Ladanyi -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/215839