Chk1 and Mps1 jointly regulate correction of merotelic kinetochore attachments

J Cell Sci. 2013 Mar 1;126(Pt 5):1235-46. doi: 10.1242/jcs.119677. Epub 2013 Jan 15.

Abstract

If uncorrected, merotelic kinetochore attachments can induce mis-segregated chromosomes in anaphase. We show that checkpoint kinase 1 (Chk1) protects vertebrate cells against merotelic attachments and lagging chromosomes and is required for correction of merotelic attachments during a prolonged metaphase. Decreased Chk1 activity leads to hyper-stable kinetochore microtubules, unstable binding of MCAK, Kif2b and Mps1 to centromeres or kinetochores and reduced phosphorylation of Hec1 by Aurora-B. Phosphorylation of Aurora-B at serine 331 (Ser331) by Chk1 is high in prometaphase and decreases significantly in metaphase cells. We propose that Ser331 phosphorylation is required for optimal localization of MCAK, Kif2b and Mps1 to centromeres or kinetochores and for Hec1 phosphorylation. Furthermore, inhibition of Mps1 activity diminishes initial recruitment of MCAK and Kif2b to centromeres or kinetochores, impairs Hec1 phosphorylation and exacerbates merotelic attachments in Chk1-deficient cells. We propose that Chk1 and Mps1 jointly regulate Aurora-B, MCAK, Kif2b and Hec1 to correct merotelic attachments. These results suggest a role for Chk1 and Mps1 in error correction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase B
  • Aurora Kinases
  • Blotting, Western
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Centromere / metabolism
  • Checkpoint Kinase 1
  • Cytoskeletal Proteins
  • Fluorescent Antibody Technique, Indirect
  • Humans
  • Kinesin / genetics
  • Kinesin / metabolism
  • Kinetochores / drug effects
  • Kinetochores / metabolism*
  • Leupeptins / pharmacology
  • Mitosis / genetics
  • Mitosis / physiology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / metabolism*

Substances

  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • Leupeptins
  • NDC80 protein, human
  • Nuclear Proteins
  • Protein Kinases
  • Protein-Tyrosine Kinases
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Protein-Serine-Threonine Kinases
  • TTK protein, human
  • KIF2B protein, human
  • Kinesin
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde