Repeat expansions confer WRN dependence in microsatellite-unstable cancers

Journal article

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 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.

Authors: van Wietmarschen, N; Sridharan, S; Nathan, WJ; Tubbs, A; Chan, EM

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature
• Volume: 586
• Issue: 7828
• Pages: 292-298
• Publication date: 2020-09-30
• Acceptance date: 2020-07-16
• DOI: 10.1038/s41586-020-2769-8
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English
• Keywords: DNA damage and repair; FFR; gastrointestinal cancer