Clks 1, 2 and 4 prevent chromatin breakage by regulating the Aurora B-dependent abscission checkpoint

Nat Commun. 2016 Apr 29;7:11451. doi: 10.1038/ncomms11451.

Abstract

When chromatin is trapped at the intercellular bridge, cells delay completion of cytokinesis (abscission) to prevent chromosome breakage. Here we show that inhibition of Cdc-like kinases (Clks) 1, 2 or 4 accelerates midbody resolution in normally segregating cells and correlates with premature abscission, chromatin breakage and generation of DNA damage in cytokinesis with trapped chromatin. Clk1, Clk2 and Clk4 localize to the midbody in an interdependent manner, associate with Aurora B kinase and are required for Aurora B-serine 331 (S331) phosphorylation and complete Aurora B activation in late cytokinesis. Phosphorylated Aurora B-S331 localizes to the midbody centre and is required for phosphorylation and optimal localization of the abscission protein Chmp4c. In addition, expression of phosphomimetic mutants Aurora B-S331E or Chmp4c-S210D delays midbody disassembly and prevents chromatin breakage in Clk-deficient cells. We propose that Clks 1, 2 and 4 impose the abscission checkpoint by phosphorylating Aurora B-S331 at the midbody.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase B / antagonists & inhibitors
  • Aurora Kinase B / genetics*
  • Aurora Kinase B / metabolism
  • Cell Line, Tumor
  • Chromatin / chemistry*
  • Chromatin / metabolism
  • Chromosome Segregation
  • Cloning, Molecular
  • Cytokinesis / genetics
  • DNA Damage
  • Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Mutation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction

Substances

  • Chromatin
  • Endosomal Sorting Complexes Required for Transport
  • RNA, Small Interfering
  • Recombinant Proteins
  • Snf7-3 protein, human
  • Clk dual-specificity kinases
  • Protein-Tyrosine Kinases
  • AURKB protein, human
  • Aurora Kinase B
  • Protein-Serine-Threonine Kinases