TY - JOUR
T1 - 5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion
AU - Bhuvanagiri, M.
AU - Lewis, J.
AU - Putzker, K.
AU - Becker, J. P.
AU - Leicht, S.
AU - Krijgsveld, J.
AU - Batra, R.
AU - Turnwald, B.
AU - Jovanovic, B.
AU - Hauer, C.
AU - Sieber, J.
AU - Hentze, M. W.
AU - Kulozik, A. E.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - 5-azacytidine MYC nonsense-mediated decay premature termination codons MESSENGER-RNA DECAY GENE-EXPRESSION MYELODYSPLASTIC SYNDROMES SURVEILLANCE PATHWAY THERAPEUTIC APPROACH PROTEIN-SYNTHESIS CYSTIC-FIBROSIS P53 MUTATIONS IN-VIVO C-MYC
U2 - 10.15252/emmm.201404461
DO - 10.15252/emmm.201404461
M3 - Journal article
SN - 1757-4676
VL - 6
SP - 1593
EP - 1609
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 12
ER -