Repeat expansions confer WRN dependence in microsatellite-unstable cancers

Niek 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 C. West, Peter J. McHugh, Paul S. Meltzer, Adam J. Bass and André Nussenzweig ()
Additional contact information
Niek van Wietmarschen: National Cancer Institute, NIH
Sriram Sridharan: National Cancer Institute, NIH
William J. Nathan: National Cancer Institute, NIH
Anthony Tubbs: National Cancer Institute, NIH
Edmond M. Chan: Dana-Farber Cancer Institute, Harvard Medical School
Elsa Callen: National Cancer Institute, NIH
Wei Wu: National Cancer Institute, NIH
Frida Belinky: National Cancer Institute, NIH
Veenu Tripathi: National Cancer Institute, NIH
Nancy Wong: National Cancer Institute, NIH
Kyla Foster: Broad Institute of Harvard and MIT
Javad Noorbakhsh: Broad Institute of Harvard and MIT
Kiran Garimella: Broad Institute of Harvard and MIT
Abimael Cruz-Migoni: University of Oxford, John Radcliffe Hospital
Joshua A. Sommers: National Institute on Aging, NIH
Yongqing Huang: Broad Institute of Harvard and MIT
Ashir A. Borah: Broad Institute of Harvard and MIT
Jonathan T. Smith: Broad Institute of Harvard and MIT
Jeremie Kalfon: Broad Institute of Harvard and MIT
Nikolas Kesten: Dana-Farber Cancer Institute, Harvard Medical School
Kasper Fugger: The Francis Crick Institute
Robert L. Walker: National Cancer Institute, NIH
Egor Dolzhenko: Illumina Inc.
Michael A. Eberle: Illumina Inc.
Bruce E. Hayward: National Institute of Diabetes, Digestive and Kidney Diseases, NIH
Karen Usdin: National Institute of Diabetes, Digestive and Kidney Diseases, NIH
Catherine H. Freudenreich: Tufts University
Robert M. Brosh: National Institute on Aging, NIH
Stephen C. West: The Francis Crick Institute
Peter J. McHugh: University of Oxford, John Radcliffe Hospital
Paul S. Meltzer: National Cancer Institute, NIH
Adam J. Bass: Dana-Farber Cancer Institute, Harvard Medical School
André Nussenzweig: National Cancer Institute, NIH

Nature, 2020, vol. 586, issue 7828, 292-298

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2769-8

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