Department of Pharmacological Sciences, State University of New York at Stony Brook, Basic Sciences Tower 8-125, 101 Nicolls Rd, Stony Brook, NY, 11794, USA.
Stony Brook Cancer Center and Renaissance School of Medicine, Stony Brook University, Basic Sciences Tower 8-125, 101 Nicolls Rd, Stony Brook, NY, 11794, USA.
Cell Mol Life Sci. 2023 Mar 9;80(4):84. doi: 10.1007/s00018-023-04738-3.
Accurate replication of the genome is fundamental to cellular survival and tumor prevention. The DNA replication fork is vulnerable to DNA lesions and damages that impair replisome progression, and improper control over DNA replication stress inevitably causes fork stalling and collapse, a major source of genome instability that fuels tumorigenesis. The integrity of the DNA replication fork is maintained by the fork protection complex (FPC), in which TIMELESS (TIM) constitutes a key scaffold that couples the CMG helicase and replicative polymerase activities, in conjunction with its interaction with other proteins associated with the replication machinery. Loss of TIM or the FPC in general results in impaired fork progression, elevated fork stalling and breakage, and a defect in replication checkpoint activation, thus underscoring its pivotal role in protecting the integrity of both active and stalled replication forks. TIM is upregulated in multiple cancers, which may represent a replication vulnerability of cancer cells that could be exploited for new therapies. Here, we discuss recent advances on our understanding of the multifaceted roles of TIM in DNA replication and stalled fork protection, and how its complex functions are engaged in collaboration with other genome surveillance and maintenance factors.
准确复制基因组是细胞存活和肿瘤预防的基础。DNA 复制叉容易受到损害 DNA 损伤和病变的影响，这些损伤会阻碍复制体的前进，如果不能正确控制 DNA 复制压力，必然会导致叉停顿和崩溃，这是引发基因组不稳定性的主要原因之一，也是肿瘤发生的主要原因。叉保护复合物（FPC）维持 DNA 复制叉的完整性，其中 TIMESLESS（TIM）构成了一个关键支架，将 CMG 解旋酶和复制聚合酶活性结合在一起，同时与其他与复制机制相关的蛋白质相互作用。TIM 或 FPC 的缺失通常会导致叉进展受损、叉停顿和断裂增加，以及复制检查点激活缺陷，从而突出了其在保护活跃和停顿复制叉完整性方面的关键作用。TIM 在多种癌症中上调，这可能代表癌细胞的复制脆弱性，可以利用这一弱点开发新的治疗方法。在这里，我们讨论了最近对 TIM 在 DNA 复制和停顿叉保护中的多方面作用的理解的进展，以及它的复杂功能如何与其他基因组监测和维持因素协同作用。
