Phospho-H2A and cohesin specify distinct tension-regulated Sgo1 pools at kinetochores and inner centromeres

Curr Biol. 2013 Oct 7;23(19):1927-33. doi: 10.1016/j.cub.2013.07.078. Epub 2013 Sep 19.

Abstract

Accurate chromosome segregation requires coordination between the dissolution of sister-chromatid cohesion and the establishment of proper kinetochore-microtubule attachment. During mitosis, sister-chromatid cohesion at centromeres enables the biorientation of and tension across sister kinetochores. The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl. Cleavage of centromeric cohesin by separase allows sister chromatids connected to microtubules from opposing poles to be evenly partitioned into daughter cells. The centromeric localization of Sgo1 requires histone H2A phosphorylation at T120 (H2A-pT120) by the kinase Bub1. The exact role of H2A-pT120 in Sgo1 regulation is, however, unclear. Here, we show that cohesin and H2A-pT120 specify two distinct pools of Sgo1-P2A at inner centromeres and kinetochores, respectively, in human cells. Bub1 inactivation delocalizes cohesin-Sgo1 to chromosome arms. Kinetochore tension triggers Sgo1 dephosphorylation and redistributes Sgo1 from inner centromeres to kinetochores. Incomplete Sgo1 redistribution causes chromosome nondisjunction. Our study suggests that Bub1-mediated H2A phosphorylation penetrates kinetochores and that this histone mark contributes to a tension-sensitive Sgo1-based molecular switch for chromosome segregation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Centromere / metabolism*
  • Chromatids / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Chromosome Segregation
  • HeLa Cells
  • Histones / metabolism*
  • Humans
  • Kinetochores / metabolism*
  • Mice
  • Microtubules / metabolism
  • Mitosis
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein Phosphatase 2 / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • RNA Interference
  • RNA, Small Interfering

Substances

  • Adaptor Proteins, Signal Transducing
  • CDCA5 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Histones
  • MYC protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • SGO1 protein, human
  • WAPL protein, human
  • cohesins
  • BUB1 protein, human
  • Protein-Serine-Threonine Kinases
  • Protein Phosphatase 2