Abstract
Cells with MSI accumulate unstable, structure-forming (TA)n repeats resolvable by the helicase WRN.
Major Finding: Cells with MSI accumulate unstable, structure-forming (TA)n repeats resolvable by the helicase WRN.
Concept: Repeat expansion led to stalled replication forks and chromosome breakage in the absence of WRN.
Impact: This study reveals why microsatellite-unstable cells require WRN and supports WRN as a drug target.
As a result of defective DNA mismatch repair, some cancer cells exhibit microsatellite instability (MSI), a predisposition to frequent mutations resulting in expansion or contraction of DNA elements called microsatellites, which are short, repetitive sequences scattered throughout the genome. The RecQ-family helicase WRN has been identified as a dependency in MSI-high cancer cells, but restoring DNA mismatch repair in these cells does not completely alleviate the requirement for WRN. In MSI-high human colon carcinoma cells, van Wietmarschen, Sridharan, Nathan, Tubbs, Chan, and colleagues found that shRNA-mediated WRN silencing caused ubiquitous chromosome shattering, an effect not observed in microsatellite-stable (MSS) cells. MSI-high cells harbored few endogenous DNA double-strand breaks (DSB) but had extensive DSBs at specific genomic loci following shRNA- or siRNA-mediated WRN depletion; again, this effect was not seen in MSS cells. Specifically, in MSI-high cells, DNA DSBs preferentially affected regions around (TA)n dinucleotide repeats, which have previously been shown in some organisms to form cruciform structures if they consist of 20 to 22 or more repeat units. Mechanistically, a protein complex containing the structure-specific endonuclease subcomplex MUS81–EME1 and the scaffold protein SLX4 was the source of the DNA DSBs observed around (TA)n dinucleotide repeats. Detection of stalled replication forks around (TA)n-repeat loci induced by the generation of non–B-form DNA secondary structures in these genomic regions triggered phosphorylation-based activation of the checkpoint kinase ATR, which subsequently recruited WRN to resolve the stalled forks via its helicase activity. Notably, (TA)n-repeat regions underwent extensive repeat expansion in MSI-high cells, leading to accumulation of non–B-form DNA structures throughout the genome and explaining why these cells required WRN. Collectively, these results reveal the molecular mechanism underlying WRN dependency in MSI-high cancer cells and suggest that WRN may be an effective therapeutic target.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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