Inherited DNA lesions determine G1 duration in the next cell cycle

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.复制应激（replication stress）是DNA损伤的主要来源，亦是癌症发生的重要驱动因素。轻度复制应激下产生的复制中间体（replication intermediates）常可逃脱细胞周期检验点（cell cycle checkpoint）的监控，并通过有丝分裂（mitosis）传递至下一个细胞周期。此类由前代传递的DNA损伤对细胞命运与存活的影响目前尚不明确。本研究通过延时显微镜（time-lapse microscopy）与定量成像细胞术（quantitative image-based cytometry），同时监测由基因组守护者蛋白53BP1标记的前代传递DNA损伤以及细胞周期进程，结果表明，前代S期（S-phase）遗留的、经53BP1标记的DNA损伤的传递，与下一个细胞周期内G1期（G1 phase）时长延长显著相关。上述结果提示，细胞间S期启动的异质性至少部分由单个细胞内复制来源的遗传DNA损伤负荷所决定。本研究进一步发现，抑癌蛋白p53的缺失可抵消复制应激诱导的G1期延长，使细胞可在携带过量遗传DNA损伤的情况下进入S期。因此，复制应激与p53缺失可能在癌症发生过程中协同发挥作用，通过促使细胞在携带前代细胞周期遗留的未修复致突变性DNA损伤的情况下重新进入细胞周期。