Chromosome missegregation during anaphase triggers p53 cell cycle arrest through histone H3.3 Ser31 phosphorylation
Chromosome missegregation during anaphase triggers p53 cell cycle arrest through histone H3.3 Ser31 phosphorylation
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DOI：
10.1038/ncb3348
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发表时间：
2016-06-01
影响因子：
21.3
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
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作者：
Hinchcliffel, Edward H.;Day, Charles A.;Dong, Zigang
定向异常的染色体可以避开纺锤体组装检查点，产生非整倍体，这是肿瘤发生的共同特征(1-4)。但是，未转化细胞中的染色体错误分离触发了一种依赖于p53的失效安全机制，该机制阻止了无意中变成非整倍体的正常细胞的增殖(5，6)。这种故障保险是如何触发的还不得而知(7，8)。在这里，我们确定了一种保守的反馈机制，通过Ser31(9)上组蛋白H3.3的差异磷酸化来监测后期染色体的错误分离。我们通过在二倍体细胞中诱导短暂的染色体错误分离来做到这一点(10)。在后期，H3.3Ser31沿着滞后或错位的染色体臂被磷酸化。几分钟内，Ser31磷酸化(Ser31P)扩散到两个子细胞的所有染色单体，并持续到G1期。用抗体显微注射掩蔽H3.3Ser31P可防止非整倍体子代中P53的核积聚。以前的工作表明，异常有丝分裂过程中延长的前中期和DNA损伤可以激活P53(11-15)。我们发现，在不延长有丝分裂或DNA损伤的情况下，对染色体错误分离的反应可以激活P53。我们的研究提供了对染色体错误分离引起的非整倍体是如何正常监测和抑制的洞察。
Maloriented chromosomes can evade the spindle assembly checkpoint and generate aneuploidy, a common feature of tumorigenesis(1-4). 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(11-15). 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.