Functional Link between BRCA1 and BAP1 through Histone H2A, Heterochromatin and DNA Damage Response

BRCA1, a breast and ovarian tumor suppressor, maintains genome stability through its functions in DNA repair, cell-cycle checkpoints, heterochromatin formation and centrosome amplification. BRCA1 interacts with BARD1 to constitute a RING heterodimer-type E3 ubiquitin ligase. BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that also regulates similar cellular events, including cell-cycle control, transcription, chromatin modification and DNA damage response. Germline mutations in BRCA1 predispose individuals to breast, ovarian, fallopian tube, peritoneal, pancreatic and prostate cancers, whereas BAP1 mutations combined with certain types of DNA damage provoke malignant mesothelioma, uveal and cutaneous melanoma, lung adenocarcinoma and renal cell carcinoma. Although BAP1 was initially discovered as a BRCA1-associated protein, recent mass-spectrometric screens of BAP1 interactors failed to detect BRCA1, raising questions about their presumed endogenous interaction. However, in addition to physical interaction, new evidence indicates a functional correlation between the two proteins. This review summarizes BAP1 function in histone modification and the DNA damage response, focusing on BAP1’s relevance to BRCA1 function. An understanding of the cooperative functions between BRCA1 and BAP1 may uncover opportunities for new drug targets in a variety of related cancers.