RNA Foci, CUGBP1, and ZNF9 Are the Primary Targets of the Mutant CUG and CCUG Repeats Expanded in Myotonic Dystrophies Type 1 and Type 2
RNA Foci, CUGBP1, and ZNF9 Are the Primary Targets of the Mutant CUG and CCUG Repeats Expanded in Myotonic Dystrophies Type 1 and Type 2
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DOI：
10.1016/j.ajpath.2011.07.013
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发表时间：
2011-11-01
影响因子：
6
通讯作者：
Timchenko, Lubov
中科院分区：
文献类型：
--
作者：
Jones, Karlie;Jin, Bingwen;Timchenko, Lubov
在强直性肌营养不良1型（DM 1）和DM 2中，非编码CUG和CCUG重复序列的扩增引起复杂的分子病理学，其特征包括RNA聚集体的积累和RNA结合蛋白肌盲样1（MBNL 1）和CUG结合蛋白1（CUGBP 1）的误调节。CCUG重复序列也减少核酸结合蛋白ZNF 9的量。使用四环素（泰特）调节的表达CUG和CCUG重复序列的单克隆细胞模型，我们发现低水平的长CUG和CCUG重复序列导致细胞核和细胞质RNA聚集，同时增加CUGBP 1和减少ZNF 9。在突变体CUG/CCUG重复序列发生强聚集之前，还观察到CUGBP 1的升高和ZNF 9的降低。CUG和CCUG重复序列的降解使ZNF 9和CUGBP 1水平正常化。短和长CUG和CCUG RNA的比较表明，短重复序列的高表达形成灶并改变CUGBP 1和ZNF 9;然而，长CUG/CCUG重复序列比高水平的短重复序列更快地错误调节CUGBP 1和ZNF 9。这些数据表明，DM 1和DM 2的校正可能通过完全和有效降解CUG和CCUG重复或通过同时破坏CUG/CCUG焦点和校正CUGBP 1和ZNF 9来实现。(Am J Pathol 2011，179：2475-2489; DOI：10.1016/j.ajpath.2011.07.013）
Expansions of noncoding CUG and CCUG repeats in myotonic dystrophies type 1 (DM1) and DM2 cause complex molecular pathology, the features of which include accumulation of RNA aggregates and misregulation of the RNA-binding proteins muscleblind-like 1 (MBNL1) and CUG-binding protein 1 (CUGBP1). CCUG repeats also decrease amounts of the nucleic acid binding protein ZNF9. Using tetracycline (Tet)-regulated monoclonal cell models that express CUG and CCUG repeats, we found that low levels of long CUG and CCUG repeats result in nuclear and cytoplasmic RNA aggregation with a simultaneous increase of CUGBP1 and a reduction of ZNF9. Elevation of CUGBP1 and reduction of ZNF9 were also observed before strong aggregation of the mutant CUG/CCUG repeats. Degradation of CUG and CCUG repeats normalizes ZNF9 and CUGBP1 levels. Comparison of short and long CUG and CCUG RNAs showed that great expression of short repeats form foci and alter CUGBP1 and ZNF9; however, long CUG/CCUG repeats misregulate CUGBP1 and ZNF9 much faster than high levels of the short repeats. These data suggest that correction of DM1 and DM2 might be achieved by complete and efficient degradation of CUG and CCUG repeats or by a simultaneous disruption of CUG/CCUG foci and correction of CUGBP1 and ZNF9. (Am J Pathol 2011, 179:2475-2489; DOI: 10.1016/j.ajpath.2011.07.013)