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Inherited DNA lesions determine G1 duration in the next cell cycle

机译：遗传的DNA病变确定下一个细胞周期中的G1持续时间

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摘要

Replication stress is a major source of DNA damage and an important driver of cancer development. Replication intermediates that occur upon mild forms of replication stress frequently escape cell cycle checkpoints and can be transmitted through mitosis into the next cell cycle. The consequences of such inherited DNA lesions for cell fate and survival are poorly understood. By using time-lapse microscopy and quantitative image-based cytometry to simultaneously monitor inherited DNA lesions marked by the genome caretaker protein 53BP1 and cell cycle progression, we show that inheritance of 53BP1-marked lesions from the previous S-phase is associated with a prolonged G1 duration in the next cell cycle. These results suggest that cell-to-cell variation in S-phase commitment is determined, at least partially, by the amount of replication-born inherited DNA damage in individual cells. We further show that loss of the tumor suppressor protein p53 overrides replication stress-induced G1 prolongation and allows S-phase entry with excessive amounts of inherited DNA lesions. Thus, replication stress and p53 loss may synergize during cancer development by promoting cell cycle re-entry with unrepaired mutagenic DNA lesions originating from the previous cell cycle.
机译：复制应力是DNA损伤的主要来源和癌症发展的重要驾驶员。复制形式的复制应力的复制中间体经常逃避细胞周期检查点，并且可以通过丝分裂传递到下一个细胞周期中。这种遗传性DNA病变对细胞命运和存活的后果尚不清楚。通过使用延时显微镜和基于定量的图像的细胞计量，同时监测由基因组观察者蛋白53bp1和细胞周期进展标记的遗传性DNA病变，我们表明，从先前的S相的遗传为53bp1标记的病变与延长有关G1持续时间在下一个细胞周期中。这些结果表明，至少部分地，至少部分地确定S相承诺中的细胞对细胞变异，其在单个细胞中的复制出生的遗传性DNA损伤的量确定。我们进一步表明，肿瘤抑制蛋白P53的丧失覆盖了复制应激诱导的G1延长，并允许S相入口具有过量的遗传性DNA病变。因此，通过促进源自先前细胞周期的未填充的致突变性DNA病变，通过促进细胞周期再入，复制应力和P53损失可以在癌症发育期间促进。

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