5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion.

Abstract

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.

• Authors: Madhuri Bhuvanagiri, Joe Lewis, Kerstin Putzker, Jonas P Becker, Stefan Leicht, Jeroen Krijgsveld, Richa Batra, Brad Turnwald, Bogdan Jovanovic, Christian Hauer, Jana Sieber, Matthias W Hentze, Andreas E Kulozik
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 6 Issue 12 Pg. 1593-609 (Dec 2014) ISSN: 1757-4684 [Electronic] England
• PMID: 25319547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Codon, Nonsense
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• RNA, Messenger
• Azacitidine

Topics

• Azacitidine (pharmacology)
• Codon, Nonsense
• HeLa Cells
• Humans
• Mutation
• Nonsense Mediated mRNA Decay (drug effects)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)