The RecQ DNA helicase WRN is a synthetic lethal target for cancers with microsatellite instability (MSI), a form of genetic hypermutability arising from impaired mismatch repair 1-4 . WRN depletion induces widespread DNA double strand breaks (DSBs) in MSI cells, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which WRN protects MSI cancers from DSBs remains unclear. Here, we demonstrate that TAdinucleotide repeats are highly unstable in MSI cells and exhibit surprisingly large-scale expansions, distinct from previously described insertion/deletion mutations of a few nucleotides 5 . We show that expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and necessitate unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to MUS81 nuclease cleavage, leading to massive chromosome shattering. Thus, our study uncovers a distinct biomarker within MSI tumors that underlies the synthetic lethal dependence on WRN, thereby supporting the development of WRN-based therapeutics.
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