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HDAC 2/3 binding and deacetylation of BubR1 initiates spindle assembly checkpoint silencing
Author(s) -
Park Inai,
Kwon MiSun,
Paik Sangjin,
Kim Hyeonjong,
Lee HaeOck,
Choi Eunhee,
Lee Hyunsook
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14286
Subject(s) - acetylation , plk1 , microbiology and biotechnology , mitosis , spindle checkpoint , biology , pcaf , mitotic exit , trichostatin a , kinetochore , cancer research , histone deacetylase , spindle apparatus , histone , cell cycle , genetics , cell division , cancer , gene , cell , chromosome
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, BRCA 2 was required for HDAC 2/3 association with acetylated BubR1 in nocodazole (Noc)‐arrested cells. Plk1, PP 2A, P300/CBP‐associated factor ( PCAF ) and BubR1 were found in the mitotic BRCA 2 complex, suggesting that BRCA 2 acts as a signaling scaffold for BubR1 modification. Furthermore, we show that Plk1 is required for BRCA 2 to localize at the prometaphase kinetochore (KT). Inhibition of Plk1 resulted in the loss of BRCA 2 from the KT, and so did PCAF , consistent with the loss of BubR1 acetylation. Concordantly, BRCA 2‐dysfunctional cells exhibited resistance to trichostatin A, which was restored when BRCA 2 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 BRCA 2–BubR1 acetylation–deacetylation pathway is an important decision‐making point for the HDAC inhibitor response. Taken together, BRCA 2 is a signaling platform for BubR1, and BubR1 deacetylation is a cue for SAC silencing.