Werner syndrome ATP-dependent helicase (WRN) (WRN)

Werner helicase (WRN) is a multifunctional DNA repair enzyme and member of the RecQ helicase family that plays critical roles in maintaining genome stability and telomere integrity[1][3]. The protein functions as an ATP-dependent DNA helicase capable of unwinding diverse DNA structures including replication forks, Holliday junctions, and G-quadruplexes, and uniquely among RecQ helicases, it also possesses 3′–5′ exonuclease activity[1][6]. WRN is essential for DNA replication and telomere maintenance through direct interactions with key repair and replication proteins, and mutations in WRN cause Werner syndrome, a rare genetic disorder characterized by cancer predisposition and accelerated aging[1][3]. Recently, WRN has emerged as a promising therapeutic target for microsatellite instable (MSI-H) cancers, where loss of functional WRN creates a synthetic lethal vulnerability; the protein's ATPase activity has been identified as critical for cell survival in this cancer subtype[1][2]. Allosteric inhibitors of WRN's helicase domain that block ATP turnover while preserving DNA binding represent a novel therapeutic approach to selectively kill MSI-H cancer cells through induction of genome-destabilizing DNA damage[4].

Other names

Werner syndrome proteinRecQL2DNA helicase WRN

Drugs targeting WRN's ATP-binding and ATP hydrolysis activities (rather than exonuclease activity) are effective at inducing cell death in MSI-H cancers. Small molecule inhibitors can bind allosteric pockets that block helicase enzymatic cycling while leaving DNA binding intact. WRN inhibition induces pervasive DNA damage and loss of cell viability specifically in MSI-H but not microsatellite stable (MSS) cancer cells.