DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression.
DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression.
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DOI：
10.1038/ncomms14728
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发表时间：
2017-03-20
影响因子：
16.6
通讯作者：
Bakal C
中科院分区：
文献类型：
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作者：
Barr AR;Cooper S;Heldt FS;Butera F;Stoy H;Mansfeld J;Novák B;Bakal C
在由外源性来源如电离辐射引起的DNA损伤后，肿瘤抑制因子p53通过表达CDK抑制剂p21介导细胞周期停滞。然而，在没有外源性DNA损伤剂的情况下，p21在维持基因组稳定性中的作用尚不清楚。在这里，使用活的单细胞测量p21蛋白在增殖培养物中，我们表明，自然发生的DNA损伤发生在S期导致p53依赖性积累的p21在母亲G2和女儿G1期。高水平的p21通过CDK抑制介导G1期阻滞，而低水平的p21对G1期进展没有影响，并且泛素连接酶CRL 4Cdt 2和SCFSkp 2在G1/S转换之前偶联降解p21。数学模型显示，由CRL 4Cdt 2创建的p21开关通过保持p21水平较低来促进不可逆的S期进入，从而防止DNA损伤时过早的S期退出。因此，我们描述了p21如何调节增殖-静止决定以维持基因组稳定性。DNA损伤后的细胞周期停滞通过CDK抑制剂p21的表达实现。在这里，作者表明，在未受干扰的细胞周期中发生的自发DNA损伤导致细胞群体表现出增殖状态，p53和p21调节增殖-静止决定。
Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability. Cell cycle arrest after DNA damage is achieved by the expression of the CDK inhibitor p21. Here the authors show that spontaneous DNA damage incurred in unperturbed cell cycles, leads to cell populations exhibiting a bistable state, with p53 and p21 regulating the proliferation-quiescence decision.