Open Access5‐azacytidine inhibits nonsense‐mediated decay in a MYC ‐dependent fashion
Author(s) -
Bhuvanagiri Madhuri,
Lewis Joe,
Putzker Kerstin,
Becker Jonas P,
Leicht Stefan,
Krijgsveld Jeroen,
Batra Richa,
Turnwald Brad,
Jovanovic Bogdan,
Hauer Christian,
Sieber Jana,
Hentze Matthias W,
Kulozik Andreas E
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404461
Subject(s) - nonsense mediated decay , azacitidine , myeloid leukemia , cancer research , translation (biology) , meg3 , cytidine , biology , rna , chemistry , genetics , gene expression , gene , biochemistry , long non coding rna , messenger rna , dna methylation , enzyme , rna splicing
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 PTC s, 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.