van Wietmarschen, NiekSridharan, SriramNathan, William J.Tubbs, AnthonyChan, EdmondCallen, ElsaWu, WeiBelinky, FridaTripathi, VeenuWong, NancyFoster, KylaNoorbakhsh, JavadGarimella, KiranCruz-Migoni, AbimaelSommers, Joshua A.Huang, YongqingBorah, Ashir A.Smith, Jonathan T.Kalfon, JeremieKesten, NikolasFugger, KasperWalker, Robert L.Dolzhenko, EgorEberle, Michael A.Hayward, Bruce E.Usdin, KarenFreudenreich, Catherine H.Brosh, Robert M.West, Stephen C.McHugh, Peter J.Meltzer, Paul S.Bass, AdamNussenzweig, André2022-08-262020-09-30van Wietmarschen, Niek, Sriram Sridharan, William J. Nathan, Anthony Tubbs, Edmond Chan, Elsa Callen, Wei Wu et al. "Repeat expansions confer WRN dependence in microsatellite-unstable cancers." Nature 586, no. 7828 (2020): 292-298. DOI: 10.1038/s41586-020-2769-80028-08361476-4687https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37373069The 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 repair. 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 nucleotides. 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.en-USMultidisciplinaryJournal Article2022-08-2610.1038/s41586-020-2769-8