Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Nat Cell Biol. 2016 Jun;18(6):668-75. doi: 10.1038/ncb3348. Epub 2016 May 2.
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.
取向错误的染色体可以逃避纺锤体组装检查点，产生非整倍体，这是非肿瘤发生的常见特征。但是，非转化细胞中的染色体错误分离会触发 p53 依赖性故障安全机制，阻止偶然成为非整倍体的正常细胞增殖。目前尚不清楚这种故障安全机制是如何触发的。在这里，我们通过对有丝分裂后期分离的染色体进行差异磷酸化组蛋白 H3.3 的 Ser31 来鉴定一种保守的反馈机制。我们通过在二倍体细胞中诱导瞬时染色体错误分离来做到这一点。在有丝分裂后期，H3.3 Ser31 在滞后或错位染色体的臂上被磷酸化。几分钟内，Ser31 磷酸化（Ser31P）就会扩散到两个子细胞的所有染色单体上，并持续到 G1 期。通过抗体微注射掩盖 H3.3 Ser31P 可以防止核 p53 在非整倍体子细胞中积累。之前的工作表明，异常有丝分裂期间的延长前期和 DNA 损伤可以激活 p53。我们表明，对染色体错误分离的 p53 激活可以在没有延长的有丝分裂或 DNA 损伤的情况下发生。我们的研究提供了对染色体错误分离引起的非整倍体通常如何被监测和抑制的深入了解。
