title: Chromosome missegregation during anaphase triggers p53 cell cycle arrest through histone H3.3 Ser31 phosphorylation.
abstract: 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.
authors.affiliation: Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Hinchcliffe
authors.affiliation: Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Day
authors.affiliation: Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Kul B
authors.initials: KB
authors.lastname: Karanjeet
authors.affiliation: Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Sela
authors.initials: S
authors.lastname: Fadness
authors.affiliation: Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Langfald
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Vaughan
authors.affiliation: Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000705:Anaphase; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000378:metabolism; D020090:Chromosome Segregation / Q000235:genetics*; D002875:Chromosomes / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; D017346:Protein Serine-Threonine Kinases