Extra-S-phase DNA damage in MSI cells evades cell cycle arrest and leads to lethality upon inhibition of WRN

Recently, WRN has emerged as a synthetic lethal target in microsatellite instability (MSI) cancers, which exhibit deficiencies in the DNA mismatch repair pathway. While WRN’s helicase activity is critical for MSI cell survival, the underlying mechanism remains only partially understood.

Previous studies suggest that WRN resolves cruciform DNA structures that otherwise induce replication stress. Here, we examine the cell cycle-resolved kinetics of DNA damage following WRN inhibition in MSI cells. We show that inhibition of WRN leads to the accumulation of DNA double-strand breaks throughout the S- and G2-phases, supporting and expanding on the cruciform-resolution model.