Cancers arise due to a broad spectrum of mutations and hence have very different genetic makeups. Efforts to develop more targeted or personalized therapies rely on potential vulnerabilities of cancer cells. In this context, it was demonstrated that cancers exhibiting microsatellite instability (MSI), are sensitive to the inhibition of the WRN helicase. These cancers include both sporadic and hereditary tumors of the gastrointestinal tract as well as ovary and endometrium. WRN is not an essential protein and temporary inhibition represents a promising strategy in cancer therapy. In order to understand the basis behind the synthetic lethality, the Cejka laboratory at the IRB developed biochemical assays to gain mechanistic insights.
A previous report from the Nussenzweig laboratory (NIH, USA) demonstrated that WRN inhibition in MSI cells results in DNA breakage at sites of extended TA repeats prone to form cruciform DNA structures. In the current study just published in the EMBO Journal, Mengoli and colleagues show that cruciform structures form easily in AT repeat sequences and that the WRN helicase efficiently unfolds these pathological DNA structures, making DNA double-stranded. Surprisingly, mismatch repair proteins MutSalpha and MutSbeta can also remove cruciforms, albeit differently than WRN. Moreover, the action of MMR and WRN appears to be synergistic, suggesting a functional cooperation.
The primary author of the study is Valentina Mengoli, a postdoc in the Cejka laboratory. The study is a collaboration with the University of Oxford, CRCM in Marseille, and Roche Pharma.