Phosphorylation of the CPC by Cdk1 promotes chromosome bi-orientation

Nature. 2010 Oct 7;467(7316):719-23. doi: 10.1038/nature09390. Epub 2010 Aug 25.

Abstract

Successful partition of replicated genomes at cell division requires chromosome attachment to opposite poles of mitotic spindle (bi-orientation). Any defects in this regulation bring about chromosomal instability, which may accelerate tumour progression in humans. To achieve chromosome bi-orientation at prometaphase, the chromosomal passenger complex (CPC), composed of catalytic kinase Aurora B and regulatory components (INCENP, Survivin and Borealin), must be localized to centromeres to phosphorylate kinetochore substrates. Although the CPC dynamically changes the subcellular localization, the regulation of centromere targeting is largely unknown. Here we isolated a fission yeast cyclin B mutant defective specifically in chromosome bi-orientation. Accordingly, we identified Cdk1 (also known as Cdc2)-cyclin-B-dependent phosphorylation of Survivin. Preventing Survivin phosphorylation impairs centromere CPC targeting as well as chromosome bi-orientation, whereas phosphomimetic Survivin suppresses the bi-orientation defect in the cyclin B mutant. Survivin phosphorylation promotes direct binding with shugoshin, which we now define as a conserved centromeric adaptor of the CPC. In human cells, the phosphorylation of Borealin has a comparable role. Thus, our study resolves the conserved mechanisms of CPC targeting to centromeres, highlighting a key role of Cdk1-cyclin B in chromosome bi-orientation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aurora Kinase B
  • Aurora Kinases
  • CDC2 Protein Kinase / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Centromere / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosomes, Fungal / metabolism*
  • Chromosomes, Human / metabolism*
  • Cyclin B / genetics
  • Cyclin B / metabolism
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins / metabolism
  • Molecular Sequence Data
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Schizosaccharomyces / cytology
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / metabolism
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism*
  • Substrate Specificity
  • Survivin

Substances

  • BIRC5 protein, human
  • Bir1 protein, S pombe
  • CDCA8 protein, human
  • Carrier Proteins
  • Cdc13 protein, S pombe
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Cyclin B
  • INCENP protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • Nbl1 protein, S pombe
  • SGO1 protein, human
  • SGO2 protein, human
  • Schizosaccharomyces pombe Proteins
  • Sgo2 protein, S pombe
  • Survivin
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • ark1 protein, S pombe
  • CDC2 Protein Kinase
  • cdc2 protein, S pombe