Phosphorylation-enabled binding of SGO1-PP2A to cohesin protects sororin and centromeric cohesion during mitosis

Nat Cell Biol. 2013 Jan;15(1):40-9. doi: 10.1038/ncb2637. Epub 2012 Dec 16.

Abstract

Timely dissolution of sister-chromatid cohesion in mitosis ensures accurate chromosome segregation to guard against aneuploidy and tumorigenesis. The complex of shugoshin and protein phosphatase 2A (SGO1-PP2A) protects cohesin at centromeres from premature removal by mitotic kinases and WAPL in prophase. Here we address the regulation and mechanism of human SGO1 in centromeric cohesion protection, and show that cyclin-dependent kinase (CDK)-mediated, mitosis-specific phosphorylation of SGO1 activates its cohesion-protection function and enables its direct binding to cohesin. The phospho-SGO1-bound cohesin complex contains PP2A, PDS5 and hypophosphorylated sororin, but lacks WAPL. Expression of non-phosphorylatable sororin bypasses the requirement for SGO1-PP2A in centromeric cohesion. Thus, mitotic phosphorylation of SGO1 targets SGO1-PP2A to cohesin, promotes dephosphorylation of PDS5-bound sororin and protects centromeric cohesin from WAPL. PP2A-orchestrated, site-selective dephosphorylation of cohesin and its regulators underlies centromeric cohesion protection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amino Acid Substitution
  • CDC2 Protein Kinase / metabolism
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Centromere / metabolism
  • Chromatids / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism*
  • HeLa Cells
  • Humans
  • Mitosis*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Phosphatase 2 / metabolism*
  • Protein Processing, Post-Translational*
  • Protein Transport
  • Proto-Oncogene Proteins / metabolism
  • Threonine / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CDCA5 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • SGO1 protein, human
  • WAPAL protein, human
  • cohesins
  • Threonine
  • CDC2 Protein Kinase
  • PPP2CA protein, human
  • Protein Phosphatase 2