title: BRCA2 fine-tunes the spindle assembly checkpoint through reinforcement of BubR1 acetylation.
abstract: Germline mutations that inactivate BRCA2 promote early-onset cancer with chromosome instability. Here, we report that BRCA2 regulates the spindle assembly checkpoint (SAC). Previously, we reported that BubR1 acetylation is essential for SAC activity. In this study we show that BRCA2 recruits the PCAF acetyltransferase and aids in BubR1 acetylation during mitosis. In the absence of BRCA2, BubR1 acetylation is abolished, and the level of BubR1 decreases during mitosis. Similarly, Brca2-deficient mouse embryonic fibroblasts exhibited weak SAC activity. Transgenic mice that were engineered to have interruptions in the BRCA2-BubR1 association exhibited marked decrease of BubR1 acetylation, weakened SAC activity, and aneuploidy. These transgenic mice developed spontaneous tumors at 40% penetrance. Moreover, immunohistochemical analyses of human breast cancer specimens suggested that BRCA2 mutation and BubR1 status is closely linked. Our results provide an explanation for how mutation of BRCA2 can lead to chromosome instability without apparent mutations in SAC components.
authors.affiliation: Department of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, 599 Gwanak-Ro, Gwanak-ku, Seoul 151-742, Korea.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Choi
authors.forename: Pil-Gu
authors.initials: PG
authors.lastname: Park
authors.forename: Hae-Ock
authors.initials: HO
authors.lastname: Lee
authors.forename: Yoo-Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Wonshik
authors.initials: W
authors.lastname: Han
authors.forename: Ho Chang
authors.initials: HC
authors.lastname: Lee
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
authors.forename: Sergey
authors.initials: S
authors.lastname: Lekomtsev
authors.forename: Hyunsook
authors.initials: H
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D000818:Animals; D024682:BRCA2 Protein / Q000502:physiology*; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008938:Mitosis / Q000502:physiology; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000502:physiology*
chemical_list: D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D011994:Recombinant Proteins; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases