Nonenzymatic Role for WRN in Preserving Nascent DNA Strands after Replication Stress

WRN, the protein defective in Werner syndrome (WS), is a multifunctional nuclease involved in DNA damage repair, replication, and genome stability maintenance. It was assumed that the nuclease activities of WRN were critical for these functions. Here, we report a nonenzymatic role for WRN in preserving nascent DNA strands following replication stress. We found that lack of WRN led to shortening of nascent DNA strands after replication stress. Furthermore, we discovered that the exonuclease activity of MRE11 was responsible for the shortening of newly replicated DNA in the absence of WRN. Mechanistically, the N-terminal FHA domain of NBS1 recruits WRN to replication-associated DNA double-stranded breaks to stabilize Rad51 and to limit the nuclease activity of its C-terminal binding partner MRE11. Thus, this previously unrecognized nonenzymatic function of WRN in the stabilization of nascent DNA strands sheds light on the molecular reason for the origin of genome instability in WS individuals. [Display omitted] •WRN guards nascent DNA strands at collapsed replication forks•MRE11 degrades newly synthesized replication forks in the absence of WRN•NBS1 recruits WRN to limit the exonuclease activity of MRE11 on nascent DNA strands•WRN stabilizes Rad51 at replication-associated DNA double-strand breaks Su et al. uncover a nonenzymatic function for WRN in DNA replication, giving insight into the molecular origin of genome instability in Werner syndrome individuals. The authors find that WRN recruitment to replication-associated DNA double-strand breaks prevents excessive MRE11-mediated degradation of nascent DNA strands.