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Cell cycle inertia underlies a bifurcation in cell fates after DNA damage
Science Advances ( IF 13.6 ) Pub Date : 2021-01-13 , DOI: 10.1126/sciadv.abe3882
Jenny F Nathans 1 , James A Cornwell 1 , Marwa M Afifi 1 , Debasish Paul 1 , Steven D Cappell 1
Affiliation  

The G1-S checkpoint is thought to prevent cells with damaged DNA from entering S phase and replicating their DNA and efficiently arrests cells at the G1-S transition. Here, using time-lapse imaging and single-cell tracking, we instead find that DNA damage leads to highly variable and divergent fate outcomes. Contrary to the textbook model that cells arrest at the G1-S transition, cells triggering the DNA damage checkpoint in G1 phase route back to quiescence, and this cellular rerouting can be initiated at any point in G1 phase. Furthermore, we find that most of the cells receiving damage in G1 phase actually fail to arrest and proceed through the G1-S transition due to persistent cyclin-dependent kinase (CDK) activity in the interval between DNA damage and induction of the CDK inhibitor p21. These observations necessitate a revised model of DNA damage response in G1 phase and indicate that cells have a G1 checkpoint.



中文翻译:

细胞周期惯性是 DNA 损伤后细胞命运分叉的基础

G 1 -S 检查点被认为可以防止具有受损 DNA 的细胞进入 S 期并复制其 DNA,并有效地在 G 1 -S 转换中阻止细胞。在这里,使用延时成像和单细胞跟踪,我们发现 DNA 损伤导致高度可变和不同的命运结果。与细胞在 G 1 -S 转变时停滞的教科书模型相反,在 G 1 期触发 DNA 损伤检查点的细胞会返回静止期,并且这种细胞重新路由可以在 G 1 期的任何时间开始。此外,我们发现大多数在 G 1阶段受到损伤的细胞实际上并没有停止并继续通过 G 1由于在 DNA 损伤和 CDK 抑制剂 p21 的诱导之间存在持续的细胞周期蛋白依赖性激酶 (CDK) 活性而导致的 -S 转变。这些观察结果需要修正 G 1期 DNA 损伤反应模型,并表明细胞具有 G 1检查点。

更新日期:2021-01-14
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