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

Edward H Hinchcliffe, Charles A Day, Kul B. Karanjeet, Sela Fadness, Alyssa Langfald, Kevin T. Vaughan, Zigang Dong

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


Maloriented chromosomes can evade the spindle assembly checkpoint and generate aneuploidy, a common feature of tumorigenesis. But chromosome missegregation in non-transformed cells triggers a p53-dependent fail-safe mechanism that blocks proliferation of normal cells that inadvertently become aneuploid. How this fail-safe is triggered is not known. Here we identify a conserved feedback mechanism that monitors missegregating chromosomes during anaphase through the differential phosphorylation of histone H3.3 at Ser31. We do this by inducing transient chromosome missegregation in diploid cells. During anaphase, H3.3 Ser31 is phosphorylated along the arms of lagging or misaligned chromosomes. Within minutes, Ser31 phosphorylation (Ser31P) spreads to all of the chromatids of both daughter cells, which persists into G1. Masking H3.3 Ser31P by antibody microinjection prevents nuclear p53 accumulation in the aneuploid daughters. Previous work demonstrated that prolonged prometaphase and DNA damage during abnormal mitosis can activate p53. We show that p53 activation in response to chromosome missegregation can occur without prolonged mitosis or DNA damage. Our study provides insight into how aneuploidy caused by chromosome missegregation is normally monitored and suppressed.

Original languageEnglish (US)
Pages (from-to)668-675
Number of pages8
JournalNature Cell Biology
Issue number6
StatePublished - Jun 1 2016

Bibliographical note

Funding Information:
This work was supported by the Hormel Foundation, Austin 'Paint the Town Pink', US Department of Defense (CDMRP) grant CA130436 to E.H.H. and National Institutes of Health grant R01 CA166011 to Z.D.


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