a Department of Molecular Mechanisms of Disease , University of Zurich , Zurich , CH , Switzerland.
Cell Cycle. 2018;17(1):24-32. doi: 10.1080/15384101.2017.1383578. Epub 2017 Nov 9.
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.
复制压力是 DNA 损伤的主要来源，也是癌症发展的重要驱动因素。在轻度复制压力下产生的复制中间体经常逃避细胞周期检查点，并可以通过有丝分裂传递到下一个细胞周期。这种遗传 DNA 损伤对细胞命运和存活的后果知之甚少。通过使用延时显微镜和基于定量图像的细胞计量术，我们可以同时监测由基因组守护者蛋白 53BP1 标记的遗传 DNA 损伤和细胞周期进程，结果表明，从前一个 S 期遗传的 53BP1 标记损伤与下一个细胞周期中 G1 期的延长有关。这些结果表明，S 期承诺的细胞间变异至少部分取决于单个细胞中复制产生的遗传 DNA 损伤的数量。我们进一步表明，肿瘤抑制蛋白 p53 的缺失会消除复制压力诱导的 G1 期延长，并允许在有大量遗传 DNA 损伤的情况下进入 S 期。因此，复制压力和 p53 缺失可能通过促进带有源自前一个细胞周期的突变 DNA 损伤的未修复细胞周期重新进入而在癌症发展过程中协同作用。
