ZNF9 activation of IRES-mediated translation of the human ODC mRNA is decreased in myotonic dystrophy type 2.
ZNF9 activation of IRES-mediated translation of the human ODC mRNA is decreased in myotonic dystrophy type 2.
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DOI：
10.1371/journal.pone.0009301
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发表时间：
2010-02-18
期刊：
影响因子：
3.7
通讯作者：
Link AJ
中科院分区：
文献类型：
--
作者：
Sammons MA;Antons AK;Bendjennat M;Udd B;Krahe R;Link AJ
肌强直性营养不良1型和2型（DM1和DM2）是具有相似临床和分子表现的肌肉营养不良形式，如肌强直、肌无力、心脏异常、白内障以及肌核中存在明确的含rna灶。DM2是由ZNF9的第一个内含子内的四核苷酸CCTG重复扩增引起的，尽管扩增的核苷酸重复引起DM2衰弱症状的机制尚不清楚。相互矛盾的研究导致了导致与DM2相关问题的机制的两种模型。首先，功能获得疾病模型假设转录RNA中的重复扩增不会直接影响ZNF9的功能。相反，含有重复序列的rna被认为将蛋白质隔离在细胞核中，导致正常细胞过程的失调。在替代模型中，重复扩增损害ZNF9功能，导致翻译水平下降。在这里，我们检查了ZNF9的正常体内功能。我们报道ZNF9与主动翻译核糖体相关，并作为人类ODC mRNA的帽无关翻译的激活因子。这种活性是通过ZNF9直接结合ODC mRNA 5'UTR内核糖体进入位点序列（IRES）介导的。ZNF9可以激活ires介导的ODC在原代人成肌细胞中的翻译，而这种活性在DM2患者的成肌细胞中降低。这些数据表明ZNF9是帽无关翻译的调节因子，并表明ZNF9活性可能在机制上促进了2型肌强直性营养不良表型。
Myotonic dystrophy types 1 and 2 (DM1 and DM2) are forms of muscular dystrophy that share similar clinical and molecular manifestations, such as myotonia, muscle weakness, cardiac anomalies, cataracts, and the presence of defined RNA-containing foci in muscle nuclei. DM2 is caused by an expansion of the tetranucleotide CCTG repeat within the first intron of ZNF9, although the mechanism by which the expanded nucleotide repeat causes the debilitating symptoms of DM2 is unclear. Conflicting studies have led to two models for the mechanisms leading to the problems associated with DM2. First, a gain-of-function disease model hypothesizes that the repeat expansions in the transcribed RNA do not directly affect ZNF9 function. Instead repeat-containing RNAs are thought to sequester proteins in the nucleus, causing misregulation of normal cellular processes. In the alternative model, the repeat expansions impair ZNF9 function and lead to a decrease in the level of translation. Here we examine the normal in vivo function of ZNF9. We report that ZNF9 associates with actively translating ribosomes and functions as an activator of cap-independent translation of the human ODC mRNA. This activity is mediated by direct binding of ZNF9 to the internal ribosome entry site sequence (IRES) within the 5′UTR of ODC mRNA. ZNF9 can activate IRES-mediated translation of ODC within primary human myoblasts, and this activity is reduced in myoblasts derived from a DM2 patient. These data identify ZNF9 as a regulator of cap-independent translation and indicate that ZNF9 activity may contribute mechanistically to the myotonic dystrophy type 2 phenotype.
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DOI：
10.1083/jcb.200206020
发表时间：
2002-11-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
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影响因子：
2.7
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DOI：
10.1523/jneurosci.1983-09.2009
发表时间：
2009-07-15
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
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作者：
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影响因子：
7
作者：
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通讯作者：
Link, Andrew J.