5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion

Nonsense‐mediated RNA decay (NMD) is an RNA‐based quality control mechanism that eliminates transcripts bearing premature translation termination codons (PTC). Approximately, one‐third of all inherited disorders and some forms of cancer are caused by nonsense or frame shift mutations that introduce PTCs, and NMD can modulate the clinical phenotype of these diseases. 5‐azacytidine is an analogue of the naturally occurring pyrimidine nucleoside cytidine, which is approved for the treatment of myelodysplastic syndrome and myeloid leukemia. Here, we reveal that 5‐azacytidine inhibits NMD in a dose‐dependent fashion specifically upregulating the expression of both PTC‐containing mutant and cellular NMD targets. Moreover, this activity of 5‐azacytidine depends on the induction of MYC expression, thus providing a link between the effect of this drug and one of the key cellular pathways that are known to affect NMD activity. Furthermore, the effective concentration of 5‐azacytidine in cells corresponds to drug levels used in patients, qualifying 5‐azacytidine as a candidate drug that could potentially be repurposed for the treatment of Mendelian and acquired genetic diseases that are caused by PTC mutations. Synopsis The clinically approved drug 5‐azacytidine inhibits nonsense‐mediated decay (NMD) through a MYC‐dependent mechanism. This supports its repurposing to treat Mendelian or acquired genetic diseases that may benefit from NMD inhibition. 5‐azacytidine is medically licensed and has been used for the treatment of some forms of leukemia for many years. Nonsense‐mediated decay (NMD) can be inhibited by 5‐azacytidine via a MYC‐dependent mechanism at concentrations that correspond to drug levels in patients. 5‐azacytidine might thus be repurposed for the treatment of Mendelian or acquired genetic diseases that may benefit from an inhibition of NMD. Graphical Abstract The clinically approved drug 5‐azacytidine inhibits nonsense‐mediated decay (NMD) through a MYC‐dependent mechanism. This supports its repurposing to treat Mendelian or acquired genetic diseases that may benefit from NMD inhibition.