title: Functional Link between BRCA1 and BAP1 through Histone H2A, Heterochromatin and DNA Damage Response.
abstract: 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.
authors.forename: Takayo
authors.initials: T
authors.lastname: Fukuda
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tsuruga
authors.forename: Takako
authors.initials: T
authors.lastname: Kuroda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki, 216-8511, Japan. to@marianna-u.ac.jp.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004249:DNA Damage; D015195:Drug Design; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063146:Polycomb-Group Proteins / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C400134:BAP1 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D006570:Heterochromatin; D006657:Histones; D063146:Polycomb-Group Proteins; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase