WRN as a Novel Target of Synthetic Lethality: Current Advances and Future Perspectives

Werner syndrome (WS) is an autosomal recessive disorder caused by mutations in the Werner syndrome protein (WRN, also known as RecQ3) gene. As a pivotal member of the RecQ DNA helicase family, WRN facilitates essential processes in DNA replication, recombination, and repair, thus safeguarding genomic stability. In this perspective, we provide a critical analysis of WRN's structural and biological features as well as its regulatory networks. Synthetic lethality strategies targeting WRN show promise for treating microsatellite instability-high (MSI-H) cancers. We further spotlight recent developments in the discovery and design of WRN inhibitors, underlining their potential therapeutic applications.