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Significance G-quadruplexes (G4) are 4-stranded nucleic acid secondary structures.MYC is a critical oncogene with a G4 in its promoter (MycG4), which acts as a transcription silencer. MycG4 is very stable and the pathological activation ofMYC in cancers requires its active unfolding. We reveal herein that DDX5, a founding member of the DEAD-box RNA helicase family, can unfold DNA G4s. The unfolding mechanism of DDX5 is distinct from previously characterized G4 helicases. Importantly, DDX5 activatesMYC gene transcription by proficiently unfolding the promoter MycG4. DDX5 is overexpressed in cancers and the DDX5–MycG4 interaction can be inhibited by small molecules to downregulateMYC . Therefore, our results suggest a new molecular target to suppressMYC for cancer intervention.

DDX5 helicase resolves G-quadruplex and is involved in MYC gene transcriptional activation