Figure 2.

Diagram depicting the mechanism of WRN-mediated replication fork stabilization. WRN is recruited to the sites of collapsed replication forks and is phosphorylated at multiple Ser/Thr sites by ATM, ATR and CDK1 kinases. WRN binding to perturbed replication forks not only stabilizes RAD51 but also prevents excessive nuclease activities of MRE11 and/or EXO1. Eventually, WRN is degraded by the ubiquitin-dependent proteasomal pathway, resulting in the protection of newly replicated genome, chromosome stability and suppression of premature senescence. In the absence of WRN, replication forks will be degraded by MRE11 and/or EXO1, and that will lead to genomic instability and premature senescence. HR—homologous recombination; EXO1—exonuclease 1; RPA—replication protein A; EME1-essential meiotic structure-specific endonuclease 1; red P—phosphorylation events; ⏊-represents blocking of nuclease activities.