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Chromosome missegregation during anaphase triggers p53 cell cycle arrest through histone H3.3 Ser31 phosphorylation

Edward H Hinchcliffe1, Charles A Day1, Kul B Karanjeet1

  • 1Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.

Nature Cell Biology
|May 3, 2016
PubMed

Insights

A novel feedback mechanism monitors chromosome missegregation via histone H3.3 phosphorylation, activating the p53 pathway to suppress aneuploidy in normal cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Aneuploidy, often caused by maloriented chromosomes, is linked to tumorigenesis.
  • A p53-dependent fail-safe mechanism normally prevents proliferation of aneuploid non-transformed cells.
  • The trigger for this fail-safe mechanism in response to chromosome missegregation was previously unknown.

Purpose of the Study:

  • To identify the conserved feedback mechanism that monitors missegregating chromosomes.
  • To elucidate how chromosome missegregation triggers the p53-dependent fail-safe.

Main Methods:

  • Inducing transient chromosome missegregation in diploid cells.
  • Analyzing histone H3.3 phosphorylation at Serine 31 (Ser31) during anaphase.
  • Utilizing antibody microinjection to mask Ser31 phosphorylation (Ser31P).

Main Results:

  • Chromosome missegregation triggers differential phosphorylation of histone H3.3 at Ser31 during anaphase.
  • Ser31 phosphorylation (Ser31P) spreads to all chromatids and persists into G1.
  • Masking Ser31P prevents nuclear p53 accumulation in aneuploid daughter cells.
  • p53 activation can occur without prolonged mitosis or DNA damage.

Conclusions:

  • A conserved feedback mechanism involving H3.3 Ser31 phosphorylation monitors chromosome missegregation.
  • This phosphorylation event is crucial for triggering p53 activation and suppressing aneuploidy.
  • The findings reveal a novel pathway for aneuploidy surveillance in normal cells.

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