Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy
Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy
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DOI：
10.1093/hmg/8.1.53
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发表时间：
1999-01-01
影响因子：
3.5
通讯作者：
Timchenko, LT
中科院分区：
文献类型：
--
作者：
Lu, XH;Timchenko, NA;Timchenko, LT
强直性肌营养不良(DM)是一种与肌钙蛋白激酶基因(DMPK)CTG三联体重复扩增相关的神经肌肉疾病，我们先前提出了一种假说，认为扩增的CUG重复隔离特定的RNA结合蛋白，这种隔离导致DM患者影响的多个组织中含有CUG重复的几个RNA的RNA处理异常。CUG结合蛋白的成员之一，CUG-BP，已被发现。在这里，我们描述了该家族的第二个成员，elav型核糖核蛋白(ETR-3)，它在心脏中高度表达，并能够与CUG重复序列相互作用。用CUG-BP探针筛选小鼠肝脏cDNA文库，鉴定出两个metr-3cDNAs，通过RT-PCR扩增出另外两个小鼠心脏cDNAs，这两个cDNAs可能是通过选择性剪接产生的。小鼠ETR-3的MEL，wt为50 kDa，与CUG-BP蛋白有很高的同源性，ETR-3分子内的RNA结合域(RBD)的组织类似于CUG-BP内的RNA结合域，对MetR-3 RNA结合活性的研究表明，MetR-3与(CUG)(8)重复结合。对metr-3的序列分析表明，在metr-3mRNA中存在几个CUG重复序列，CUG-BP和metr-3都通过CUG重复序列与metr-3mRNA结合，提示CUG-BP样蛋白可能参与了metr-3加工的调控。对ETR-3的组织分布分析表明，在人类细胞中，ETR-3mRNA在心脏中高表达，但在其他被检测的组织中检测不到。我们的结果表明，存在一组与CUG重复序列结合的蛋白质家族，并可能受到CUG重复序列扩张的影响。
Myotonic dystrophy (DM) is a neuromuscular disorder associated with CTG triplet repeat expansion in the myotonin protein kinase gene (DMPK), We previously proposed a hypothesis suggesting that the expanded CUG repeats sequester specific RNA-binding proteins and that such a sequestration results in abnormal RNA processing of several RNAs containing CUG repeats in multiple tissues affected in patients with DM. One of the members of the CUG-binding proteins, CUG-BP, has been identified previously. Here we describe the second member of this family, elav-type ribonucleoprotein (ETR-3), which is highly expressed in heart and is able to interact with CUG repeats. Screening of a mouse liver cDNA library with a CUG-BP probe identified two mETR-3 cDNAs, Two additional cDNAs from mouse heart were amplified by RT-PCR, These cDNAs differ by several insertions/deletions and might be generated via alternative splicing. Mouse ETR-3 has a mel, wt of 50 kDa and displays a high level of homology to CUG-BP protein, The organization of the RNA-binding domains (RBDs) within the ETR-3 molecule is similar to one within CUG-BP, A study of mETR-3 RNA-binding activity showed that the mETR-3 binds to (CUG)(8) repeats. Sequence analysis of mETR-3 indicates the presence of several CUG repeats within the mETR-3 mRNA, Both CUG-BP and mETR-3 bind to mETR-3 mRNA via CUG repeats, suggesting the possible involvement of CUG-BP-like proteins in the regulation of mETR-3 processing. Analysis of the tissue distribution of ETR-3 showed that in human cells, ETR-3 mRNA is highly expressed in heart, but is undetectable in other tissues examined, Our results suggest the existence of a family of proteins that bind to CUG repeats and might be affected in DM by expansion of CUG repeats.