5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion.
5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion.
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DOI：
10.15252/emmm.201404461
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发表时间：
2014-12
影响因子：
11.1
通讯作者：
Kulozik AE
中科院分区：
文献类型：
--
作者：
Bhuvanagiri M;Lewis J;Putzker K;Becker JP;Leicht S;Krijgsveld J;Batra R;Turnwald B;Jovanovic B;Hauer C;Sieber J;Hentze MW;Kulozik AE
无意义介导的RNA衰变(NMD)是一种基于RNA的质量控制机制，它消除了带有提前翻译终止密码子(PTC)的转录本。大约三分之一的遗传性疾病和某些形式的癌症是由引入PTCs的无义或移码突变引起的，而NMD可以调节这些疾病的临床表型。5-氮胞苷是一种天然存在的嘧啶核苷胞苷的类似物，已被批准用于治疗骨髓增生异常综合征和髓系白血病。在这里，我们揭示了5-氮胞苷以剂量依赖的方式抑制NMD，特别是上调了含有PTC的突变和细胞NMD靶标的表达。此外，5-氮胞苷的这种活性依赖于MYC表达的诱导，从而在该药物的作用与已知影响NMD活性的关键细胞通路之一之间提供了联系。此外，细胞中5-氮胞苷的有效浓度与患者使用的药物水平相对应，使5-氮胞苷有资格作为候选药物，有可能被重新用于治疗由PTC突变引起的孟德尔和获得性遗传病。
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.
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影响因子：
14.9
作者：
BURKE, JF;MOGG, AE
通讯作者：
MOGG, AE
影响因子：
64.8
作者：
Dominguez-Sola, David;Ying, Carol Y.;Dalla-Favera, Riccardo
通讯作者：
Dalla-Favera, Riccardo
影响因子：
2.7
作者：
Gryn, J;Zeigler, ZR;Evans, C
通讯作者：
Evans, C
影响因子：
11.4
作者：
Ivanov, Pavel V.;Gehring, Niels H.;Kulozik, Andreas E.
通讯作者：
Kulozik, Andreas E.
影响因子：
64.8
作者：
Barna, Maria;Pusic, Aya;Zollo, Ornella;Costa, Maria;Kondrashov, Nadya;Rego, Eduardo;Rao, Pulivarthi H.;Ruggero, Davide
通讯作者：
Ruggero, Davide