Repeat expansions confer WRN dependence in microsatellite-unstable cancers
Authors listNiek van Wietmarschen Sriram Sridharan William J Nathan Anthony Tubbs Edmond M Chan Elsa Callen Wei Wu Frida Belinky Veenu Tripathi Nancy Wong Kyla Foster Javad Noorbakhsh Kiran Garimella Abimael Cruz-Migoni Joshua A Sommers Yongqing Huang Ashir A Borah Jonathan T Smith Jeremie Kalfon Nikolas Kesten Kasper Fugger Robert L Walker Egor Dolzhenko Michael A Eberle Bruce E Hayward Karen Usdin Catherine H Freudenreich Robert M Brosh Stephen West Peter J McHugh Paul S Meltzer Adam J Bass André Nussenzweig
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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.
Issue number 7828