Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York, 11794, USA.
Center for Genomic Integrity, Institute for Basic Science, Ulsan, 44919, Republic of Korea.
Nat Commun. 2020 Oct 30;11(1):5495. doi: 10.1038/s41467-020-19162-5.
Protecting replication fork integrity during DNA replication is essential for maintaining genome stability. Here, we report that SDE2, a PCNA-associated protein, plays a key role in maintaining active replication and counteracting replication stress by regulating the replication fork protection complex (FPC). SDE2 directly interacts with the FPC component TIMELESS (TIM) and enhances its stability, thereby aiding TIM localization to replication forks and the coordination of replisome progression. Like TIM deficiency, knockdown of SDE2 leads to impaired fork progression and stalled fork recovery, along with a failure to activate CHK1 phosphorylation. Moreover, loss of SDE2 or TIM results in an excessive MRE11-dependent degradation of reversed forks. Together, our study uncovers an essential role for SDE2 in maintaining genomic integrity by stabilizing the FPC and describes a new role for TIM in protecting stalled replication forks. We propose that TIM-mediated fork protection may represent a way to cooperate with BRCA-dependent fork stabilization.
在 DNA 复制过程中保护复制叉的完整性对于维持基因组稳定性至关重要。在这里，我们报告说，与 PCNA 相关的蛋白 SDE2 通过调节复制叉保护复合物（FPC）在维持活跃的复制和抵抗复制应激方面发挥着关键作用。SDE2 直接与 FPC 组件 TIMELSS（TIM）相互作用，并增强其稳定性，从而有助于 TIM 定位到复制叉并协调复制体的进展。与 TIM 缺陷一样，SDE2 的敲低导致叉突进展受损和叉突恢复停滞，同时无法激活 CHK1 磷酸化。此外，SDE2 或 TIM 的缺失会导致过多的 MRE11 依赖性逆转叉的降解。总之，我们的研究揭示了 SDE2 通过稳定 FPC 在维持基因组完整性方面的重要作用，并描述了 TIM 在保护停滞的复制叉方面的新作用。我们提出，TIM 介导的叉突保护可能代表了与 BRCA 依赖性叉突稳定合作的一种方式。
