Abstract
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.
Highlights
Protecting replication fork integrity during DNA replication is essential for maintaining genome stability
The proximity-ligation assay (PLA) assay performed with SDE2 and biotin antibodies resulted in nuclear PLA foci, indicating the presence of endogenous SDE2 localized in close proximity to biotinylated EdU-labeled active DNA replication forks (Fig. 1b, c)
It interacts with the structural maintenance of chromosomes (SMC) subunits of the cohesion complex to promote the establishment of sister chromatid cohesion (SCC) during DNA replication[30]
Summary
Protecting replication fork integrity during DNA replication is essential for maintaining genome stability. Emerging evidence suggests that fork reversal plays a key role in protecting stressed replication forks[13] This process involves regression of a stalled fork to form a four-way junction by the action of the RAD51 recombinase and several SWI/SNF family translocases such as SMARCAL1, ZRANB3, and HLTF14,15. We further showed that chromatin-associated degradation of SDE2Ct by Arg/N-end rule-p97 ATPase proteolytic pathway is necessary for propagating the signaling of the DNA replication stress response at RPA-coated stalled forks in response to UVC damage[35] These findings indicate that the dynamic control of SDE2 protein levels may modulate protein complexes and their activities at stressed forks. We propose that SDE2 fulfills an essential role in active replication by promoting the association of the FPC with the replisome and participates together with TIM in the protection of stalled forks during fork reversal
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