保持基因组稳定是健康细胞和健康生物的关键，而基因组完整性的异常维护是衰老以及与年龄相关的疾病，包括癌症和神经退行性疾病的标志。为了保持稳定的基因组，基因组监视和修复途径与细胞周期调控以及在转录和DNA复制过程中发生的DNA转录有着密切的联系。这些过程在不同的时间和长度尺度上协调进行，涉及到染色质拓扑的动态变化，脆性基因组区域和修复因子在核修复中心的聚集，核细胞骨架的动员以及细胞周期检查点的激活。在这里，我们提供了人类细胞中细胞周期调控和基因组复制过程的概述，接着介绍了复制应激和受到干扰的DNA合成引发的细胞反应。我们讨论了在高水平复制应激下经历脆性基因组区域，特别关注线性染色体末端的复制应激引起的端粒脆性。我们以癌细胞中的替代端粒长度延长（ALT）和与ALT相关的PML体（APBs）作为复制应激相关聚集DNA损伤的例子，讨论了DNA修复反应的区域化以及与相分离相关的蛋白质属性的作用。最后，我们强调了DNA修复与力学生物学之间新兴的联系，并讨论了生物分子凝胶、核细胞骨架的组分以及膜结合细胞器与无膜大分子凝胶之间的界面如何协同地在空间和时间上协调基因组维护。© 2023. 作者。

Genome stability is key for healthy cells in healthy organisms, and deregulated maintenance of genome integrity is a hallmark of aging and of age-associated diseases including cancer and neurodegeneration. To maintain a stable genome, genome surveillance and repair pathways are closely intertwined with cell cycle regulation and with DNA transactions that occur during transcription and DNA replication. Coordination of these processes across different time and length scales involves dynamic changes of chromatin topology, clustering of fragile genomic regions and repair factors into nuclear repair centers, mobilization of the nuclear cytoskeleton, and activation of cell cycle checkpoints. Here, we provide a general overview of cell cycle regulation and of the processes involved in genome duplication in human cells, followed by an introduction to replication stress and to the cellular responses elicited by perturbed DNA synthesis. We discuss fragile genomic regions that experience high levels of replication stress, with a particular focus on telomere fragility caused by replication stress at the ends of linear chromosomes. Using alternative lengthening of telomeres (ALT) in cancer cells and ALT-associated PML bodies (APBs) as examples of replication stress-associated clustered DNA damage, we discuss compartmentalization of DNA repair reactions and the role of protein properties implicated in phase separation. Finally, we highlight emerging connections between DNA repair and mechanobiology and discuss how biomolecular condensates, components of the nuclear cytoskeleton, and interfaces between membrane-bound organelles and membraneless macromolecular condensates may cooperate to coordinate genome maintenance in space and time.© 2023. The Author(s).