首页|TIP60 acetylation of Bub1 regulates centromeric H2AT120 phosphorylation for faithful chromosome segregation
TIP60 acetylation of Bub1 regulates centromeric H2AT120 phosphorylation for faithful chromosome segregation
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Proper function of the centromeres ensures correct attachment of kinetochores to spindle microtubules and faithful chromosome segre-gation in mitosis.Defects in the integrity and function of centromeres can result in chromosome missegregation and genomic instability.Bub1 is essential for the mitotic centromere dynamics,yet the underlying molecular mechanisms remain largely unclear.Here,we de-monstrate that TIP60 acetylates Bub1 at K424 and K431 on kinetochores in early mitosis.This acetylation increases the kinase activity of Bub1 to phosphorylate centromeric histone H2A at T120(H2ApT120),which recruits Aurora B and Shugoshin 1(Sgo1)to regulate centromere integrity,protect centromeric cohesion,and ensure the subsequent faithful chromosome segregation.Expression of the non-acetylated Bub1 mutant reduces its kinase activity,decreases the level of H2ApT120,and disrupts the recruitment of centromere proteins and chromosome congression,leading to genomic instability of daughter cells.When cells exit mitosis,HDAC1-regulated deacetylation of Bub1 decreases H2ApT120 levels and thereby promotes the departure of centromeric CPC and Sgo1,ensuring timely centromeres dis-assembly.Collectively,our results reveal a molecular mechanism by which the acetylation and deacetylation cycle of Bub1 modulates the phosphorylation of H2A at T120 for recruitment of Aurora B and Sgo1 to the centromeres,ensuring faithful chromosome segregation during mitosis.
The Academy for Cell and Life Health,Faculty of Life Science and Technology,Kunming University of Science and Technology,Kunming 650500,China
The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education,College of Life Sciences,Peking University,Beijing 100871,China
National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of China
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