DDX5 helicase resolves G-quadruplex and is involved in <i>MYC</i> gene transcriptional activation

Abstract

G-quadruplexes (G4) are noncanonical secondary structures formed in guanine-rich DNA and RNA sequences. <i>MYC</i>, one of the most critical oncogenes, forms a DNA G4 in its proximal promoter region (MycG4) that functions as a transcriptional silencer. However, MycG4 is highly stable in vitro and its regulatory role would require active unfolding. Here we report that DDX5, one of the founding members of the DEAD-box RNA helicase family, is extremely proficient at unfolding MycG4-DNA. Our results show that DDX5 is a highly active G4-resolvase that does not require a single-stranded overhang and that ATP hydrolysis is not directly coupled to G4-unfolding of DDX5. The chromatin binding sites of DDX5 are G-rich sequences. In cancer cells, DDX5 is enriched at the <i>MYC</i> promoter and activates <i>MYC</i> transcription. The DDX5 interaction with the <i>MYC</i> promoter and DDX5-mediated <i>MYC</i> activation is inhibited by G4-interactive small molecules. Our results uncover a function of DDX5 in resolving DNA and RNA G4s and suggest a molecular target to suppress <i>MYC</i> for cancer intervention.