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

• Published in: Nature cell biology Vol. 18; no. 6; pp. 668 - 675
• Main Authors: Hinchcliffe, Edward H., Day, Charles A., Karanjeet, Kul B., Fadness, Sela, Langfald, Alyssa, Vaughan, Kevin T., Dong, Zigang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2016; Nature Publishing Group
• Subjects: 14; 14/19; 631/80/641; 631/80/641/1655; 631/80/641/2002; 631/80/641/2187; Anaphase; Aneuploidy; Animals; Cancer Research; Cell Biology; Cell cycle; Cell Cycle Checkpoints - genetics; Cell Cycle Proteins - metabolism; Chromosome Segregation - genetics; Chromosomes; Chromosomes - metabolism; Cyclin-dependent kinases; Daughters; Deoxyribonucleic acid; Developmental Biology; DNA; DNA damage; DNA Damage - genetics; Genes, p53 - genetics; Histones - metabolism; Humans; Kinases; letter; Life Sciences; Mitosis - physiology; Observations; Phosphorylation; Properties; Protein-Serine-Threonine Kinases - metabolism; Spindle Apparatus - metabolism; Stem Cells; United States > US
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3348

Chromosome missegregation can lead to p53 activation to block proliferation of aneuploid cells. Hinchcliffe, Dong and colleagues find that generation and spreading of a histone H3.3 Ser31 phosphorylation mark mediates this response. Maloriented chromosomes can evade the spindle assembly checkpoint and generate aneuploidy, a common feature of tumorigenesis 1 , 2 , 3 , 4 . But chromosome missegregation in non-transformed cells triggers a p53-dependent fail-safe mechanism that blocks proliferation of normal cells that inadvertently become aneuploid 5 , 6 . How this fail-safe is triggered is not known 7 , 8 . Here we identify a conserved feedback mechanism that monitors missegregating chromosomes during anaphase through the differential phosphorylation of histone H3.3 at Ser31 9 . We do this by inducing transient chromosome missegregation in diploid cells 10 . 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 11 , 12 , 13 , 14 , 15 . 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.