Repeat expansions confer WRN dependence in microsatellite-unstable cancers.
van Wietmarschen N., Sridharan S., Nathan WJ., Tubbs A., Chan EM., Callen E., Wu W., Belinky F., Tripathi V., Wong N., Foster K., Noorbakhsh J., Garimella K., Cruz-Migoni A., Sommers JA., Huang Y., Borah AA., Smith JT., Kalfon J., Kesten N., Fugger K., Walker RL., Dolzhenko E., Eberle MA., Hayward BE., Usdin K., Freudenreich CH., Brosh RM., West SC., McHugh PJ., Meltzer PS., Bass AJ., Nussenzweig A.
The RecQ DNA helicase WRN is a synthetic lethal target for cancer cells with microsatellite instability (MSI), a form of genetic hypermutability that arises from impaired mismatch repair1-4. Depletion of WRN induces widespread DNA double-strand breaks in MSI cells, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which WRN protects MSI-associated cancers from double-strand breaks remains unclear. Here we show that TA-dinucleotide repeats are highly unstable in MSI cells and undergo large-scale expansions, distinct from previously described insertion or deletion mutations of a few nucleotides5. Expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and require unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to cleavage by the MUS81 nuclease, leading to massive chromosome shattering. These findings identify a distinct biomarker that underlies the synthetic lethal dependence on WRN, and support the development of therapeutic agents that target WRN for MSI-associated cancers.