Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats
Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats
复制标题
DOI：
10.1093/hmg/ddh056
复制
发表时间：
2004-03-01
影响因子：
3.5
通讯作者：
Ishiura, S
中科院分区：
文献类型：
--
作者：
Kino, Y;Mori, D;Ishiura, S
强直性肌营养不良（DM）1型是由DMPK基因中CTG重复序列的扩增引起的，2型是由ZNF 9基因中的CCTG重复序列引起的。先前的报道表明，含有扩展的CUG/CCUG重复序列的转录本可能具有毒性功能获得效应，可能影响DM发病机制中RNA结合蛋白的功能。在这里，它试图比较三种蛋白质，CUG-BP，MBNL 1/EXP和PKR的RNA结合特性，这些蛋白质以前被认为与CUG重复序列相互作用。在酵母三杂交系统中，MBNL 1与CUG和CCUG重复序列相互作用，而与CUG-BP和PKR不相互作用。通过使用各种合成RNA，发现MBNL 1与总结为CHHG和CHG重复的重复序列特异性相互作用，其中H是A、U或C。有趣的是，MBNL 1不与包含CAG/CUG重复序列的真正双链RNA相互作用，表明MBNL 1更喜欢含有凸起的双链RNA。缺失分析表明MBNL 1的剪接变体之间的RNA结合能力的差异。MBNL 1可以与ZNF 9中的重复基序结合，ZNF 9中含有最小长度的非CCUG插入的CCUG重复序列。
Myotonic dystrophy (DM) type 1 is caused by an expansion of a CTG repeat in the DMPK gene and type 2 by a CCTG repeat in the ZNF9 gene. Previous reports have suggested that transcripts containing expanded CUG/CCUG repeats might have toxic gain-of-function effects, probably affecting the function of RNA-binding proteins in the pathogenesis of DM. Here, it was attempted to compare the RNA-binding properties of three proteins, CUG-BP, MBNL1/EXP and PKR, which have previously been suggested to interact with CUG repeats. MBNL1, but not CUG-BP or PKR, interacted with both CUG and CCUG repeats in a yeast three-hybrid system. By using various synthetic RNAs, it was found that MBNL1 specifically interacts with repetitive sequences summarized as CHHG and CHG repeats, where H is A, U or C. Interestingly, MBNL1 did not interact with a genuine double-stranded RNA comprising CAG/CUG repeats, suggesting that MBNL1 prefers bulge-containing double-stranded RNAs. Deletion analysis indicates a difference in RNA-binding abilities among splice variants of MBNL1. It was also found that MBNL1 can bind to repetitive motifs in ZNF9, which contain a minimal length of CCUG repeats with non-CCUG insertions.