Repeat expansions confer WRN dependence in microsatellite-unstable cancers

  • Nature. 2020 Oct;586(7828):292-298. doi: 10.1038/s41586-020-2769-8.
Niek van Wietmarschen  #  1 ,  Sriram Sridharan  #  1 ,  William J Nathan  #  1  2 ,  Anthony Tubbs  #  1 ,  Edmond M Chan  #  3  4 ,  Elsa Callen  1 ,  Wei Wu  1 ,  Frida Belinky  1 ,  Veenu Tripathi  1 ,  Nancy Wong  1 ,  Kyla Foster  4 ,  Javad Noorbakhsh  4 ,  Kiran Garimella  4 ,  Abimael Cruz-Migoni  2 ,  Joshua A Sommers  5 ,  Yongqing Huang  4 ,  Ashir A Borah  4 ,  Jonathan T Smith  4 ,  Jeremie Kalfon  4 ,  Nikolas Kesten  6 ,  Kasper Fugger  7 ,  Robert L Walker  8 ,  Egor Dolzhenko  9 ,  Michael A Eberle  9 ,  Bruce E Hayward  10 ,  Karen Usdin  10 ,  Catherine H Freudenreich  11 ,  Robert M Brosh Jr  5 ,  Stephen C West  7 ,  Peter J McHugh  2 ,  Paul S Meltzer  8 ,  Adam J Bass  3  4 ,  André Nussenzweig  12
Affiliations
  • 1. Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
  • 2. Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  • 3. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 4. Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 5. Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA.
  • 6. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Cambridge, MA, USA.
  • 7. DNA Recombination and Repair Laboratory, The Francis Crick Institute, London, UK.
  • 8. Genetics Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
  • 9. Illumina Inc., San Diego, CA, USA.
  • 10. Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
  • 11. Department of Biology, Tufts University, Medford, MA, USA.
  • 12. Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA. [email protected].
  • # Contributed equally.
PMID: 32999459 DOI: 10.1038/s41586-020-2769-8
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.