Aurora A-dependent CENP-A phosphorylation at inner centromeres protects bioriented chromosomes against cohesion fatigue

Nat Commun. 2018 May 14;9(1):1888. doi: 10.1038/s41467-018-04089-9.

Abstract

Sustained spindle tension applied to sister centromeres during mitosis eventually leads to uncoordinated loss of sister chromatid cohesion, a phenomenon known as "cohesion fatigue." We report that Aurora A-dependent phosphorylation of serine 7 of the centromere histone variant CENP-A (p-CENP-AS7) protects bioriented chromosomes against cohesion fatigue. Expression of a non-phosphorylatable version of CENP-A (CENP-AS7A) weakens sister chromatid cohesion only when sister centromeres are under tension, providing the first evidence of a regulated mechanism involved in protection against passive cohesion loss. Consistent with this observation, p-CENP-AS7 is detected at the inner centromere where it forms a discrete domain. The depletion or inhibition of Aurora A phenocopies the expression of CENP-AS7A and we show that Aurora A is recruited to centromeres in a Bub1-dependent manner. We propose that Aurora A-dependent phosphorylation of CENP-A at the inner centromere protects chromosomes against tension-induced cohesion fatigue until the last kinetochore is attached to spindle microtubules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase A / genetics*
  • Aurora Kinase A / metabolism
  • Cell Line, Tumor
  • Centromere / metabolism*
  • Centromere / ultrastructure
  • Centromere Protein A / genetics*
  • Centromere Protein A / metabolism
  • Chromosome Segregation*
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Microtubules / metabolism
  • Microtubules / ultrastructure
  • Mitosis*
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Serine / metabolism
  • Signal Transduction
  • Spindle Apparatus / metabolism
  • Spindle Apparatus / ultrastructure

Substances

  • Centromere Protein A
  • RNA, Small Interfering
  • Serine
  • AURKA protein, human
  • Aurora Kinase A
  • BUB1 protein, human
  • Protein Serine-Threonine Kinases