MYCN and helicases DDX17 and DDX5 have opposite effects on the production of readthrough-associated chimeric transcripts

DEAD box helicases DDX17 and DDX5 control transcription termination and the associated processing of the 3' end of pre-messenger RNAs. Here, we demonstrate that the transcriptional readthrough induced by DDX17 depletion, either alone or in combination with DDX5, leads to an increased production of chimeric transcripts from tandemly oriented gene, or tracRNAs, in neuroblastoma cells. Analysis of neuroblastoma tumours in which tracRNAs are abundant revealed that low expression of DDX17 and DDX5 genes is associated with high-risk tumours and poor overall patient survival, and inversely linked with MYCN oncogene amplification. We demonstrate that changes in MYCN expression do not affect the expression of either helicase, but alter transcription termination leading to the production of tracRNAs. MYCN acts on termination through its direct binding to the 3' region of genes and it interacts with DDX17, suggesting that it may interfere with the activity of the helicase. Collectively, our work reveals a novel function of MYCN in transcription termination and suggests that the deregulation of MYCN and DDX17/DDX5 expression in neuroblastoma may lead to the expression of non-canonical and potentially harmful RNA molecules.