Tomoaki Sobajima,Luke J Fulcher,Caleb Batley,Susanna J Alsop,Jonah Veakins,Francis A Barr
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引用次数: 0
摘要
延长有丝分裂导致MDM2的破坏,在没有DNA损伤的情况下启动p53依赖性G1细胞周期阻滞。在这里,我们研究了细胞周期早期的DNA损伤如何影响这种有丝分裂计时器反应。我们发现G2-DNA损伤触发有丝分裂和有丝分裂计时器的高度渗透旁路,产生四倍体细胞在G1中被阻止。DNA损伤后G2到G1的崩溃是由p21介导的CDK2抑制引发的,并通过G2/ m -细胞周期蛋白A和b的破坏而变得不可逆。这种行为在p53-磷酸酶WIP1 (PPM1D)发生癌症相关突变的细胞中发生改变,这增加了DNA损伤信号传导的阈值,使DNA损伤的G2细胞在MDM2水平升高的情况下进入有丝分裂,从而抑制有丝分裂时间依赖的G1细胞周期停滞。重要的是,在没有DNA损伤的情况下,WIP1突变和敲除都不能阻止p53依赖性g1阻滞对有丝分裂延长的反应。因此,延长有丝分裂和G2-DNA损伤通过WIP1和基因毒性应激的不同要求的离散途径促进p53依赖性G1细胞周期退出。
WIP1 mutations suppress DNA damage triggered bypass of the mitotic timer.
Prolonged mitosis results in the destruction of MDM2, initiating a p53-dependent G1 cell-cycle arrest in the absence of DNA damage. Here, we investigate how DNA damage earlier in the cell cycle affects this mitotic-timer response. We find that G2-DNA damage triggers highly penetrant bypass of mitosis and of the mitotic timer, generating tetraploid cells arrested in G1. Collapse of G2 to G1 after DNA damage is initiated by p21-mediated CDK2 inhibition and rendered irreversible by the destruction of G2/M-cyclins A and B. This behaviour is altered in cells with cancer-associated mutations in the p53-phosphatase WIP1 (PPM1D), which increase the threshold for DNA-damage signalling, enabling DNA-damaged G2 cells to enter mitosis with elevated levels of MDM2, thereby suppressing mitotic-timer-dependent G1 cell-cycle arrest. Importantly, neither WIP1 mutations nor knockout prevent p53-dependent G1-arrest in response to prolonged mitosis in the absence of DNA damage. Prolonged mitosis and G2-DNA damage thus promote p53-dependent G1 cell-cycle exit through discrete routes with differential requirements for WIP1 and genotoxic stress.