title: 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.affiliation: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Bhuvanagiri
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Joe
authors.initials: J
authors.lastname: Lewis
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Putzker
authors.affiliation: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jonas P
authors.initials: JP
authors.lastname: Becker
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Leicht
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Krijgsveld
authors.affiliation: Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark.
authors.forename: Richa
authors.initials: R
authors.lastname: Batra
authors.affiliation: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Brad
authors.initials: B
authors.lastname: Turnwald
authors.affiliation: Centre for Molecular Biology of the University of HeidelbergUniversity of Heidelberg, Heidelberg, Germany.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Jovanovic
authors.affiliation: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hauer
authors.affiliation: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Sieber
authors.affiliation: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany European Molecular Biology Laboratory, Heidelberg, Germany hentze@embl.de andreas.kulozik@med.uni-heidelberg.de.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Hentze
authors.affiliation: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany hentze@embl.de andreas.kulozik@med.uni-heidelberg.de.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D001374:Azacitidine / Q000494:pharmacology*; D018389:Codon, Nonsense; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D059365:Nonsense Mediated mRNA Decay / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
chemical_list: D018389:Codon, Nonsense; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D001374:Azacitidine
keywords: 5‐azacytidine; MYC; nonsense‐mediated decay; premature termination codons