Person: Chan, Edmond
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
First Name
Name
Search Results
Publication Repeat expansions confer WRN dependence in microsatellite-unstable cancers
(Springer Science and Business Media LLC, 2020-09-30) van Wietmarschen, Niek; Sridharan, Sriram; Nathan, William J.; Tubbs, Anthony; Chan, Edmond; Callen, Elsa; Wu, Wei; Belinky, Frida; Tripathi, Veenu; Wong, Nancy; Foster, Kyla; Noorbakhsh, Javad; Garimella, Kiran; Cruz-Migoni, Abimael; Sommers, Joshua A.; Huang, Yongqing; Borah, Ashir A.; Smith, Jonathan T.; Kalfon, Jeremie; Kesten, Nikolas; Fugger, Kasper; Walker, Robert L.; Dolzhenko, Egor; Eberle, Michael A.; Hayward, Bruce E.; Usdin, Karen; Freudenreich, Catherine H.; Brosh, Robert M.; West, Stephen C.; McHugh, Peter J.; Meltzer, Paul S.; Bass, Adam; Nussenzweig, AndréThe 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.