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JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
HDAC2/3 binding and deacetylation of BubR1 initiates spindle assembly checkpoint silencing.
FEBS Journal 2017 December
BubR1 acetylation is essential in spindle assembly checkpoint (SAC) signaling. Here we show that BubR1 deacetylation is a signal that initiates mitotic exit. Sustained BubR1 acetylation arrests the cells in metaphase, although chromosome congression is achieved. BubR1 deacetylation was coordinated with dephosphorylation in mitotic exit, suggesting the presence of a coordinated acetylation-phosphorylation code in mitotic signaling. Histone deacetylase (HDAC) 2 and 3 bound to acetylated BubR1 exclusively in mitosis and led to the polyubiquitination of BubR1. Subsequent degradation of BubR1 resulted in the disassembly of the mitotic checkpoint complex. Importantly, BRCA2 was required for HDAC2/3 association with acetylated BubR1 in nocodazole (Noc)-arrested cells. Plk1, PP2A, P300/CBP-associated factor (PCAF) and BubR1 were found in the mitotic BRCA2 complex, suggesting that BRCA2 acts as a signaling scaffold for BubR1 modification. Furthermore, we show that Plk1 is required for BRCA2 to localize at the prometaphase kinetochore (KT). Inhibition of Plk1 resulted in the loss of BRCA2 from the KT, and so did PCAF, consistent with the loss of BubR1 acetylation. Concordantly, BRCA2-dysfunctional cells exhibited resistance to trichostatin A, which was restored when BRCA2 was introduced. That loss of Brca2 conferred resistance to various HDAC inhibitors was corroborated by the experiments in mouse pancreatic organoids. These results suggest that the BRCA2-BubR1 acetylation-deacetylation pathway is an important decision-making point for the HDAC inhibitor response. Taken together, BRCA2 is a signaling platform for BubR1, and BubR1 deacetylation is a cue for SAC silencing.
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