期刊
EMBO JOURNAL
卷 25, 期 18, 页码 4271-4283出版社
WILEY
DOI: 10.1038/sj.emboj.7601296
关键词
CUG-BP1; hnRNP H; muscleblind; myotonic dystrophy 1; splicing
资金
- NCI NIH HHS [P30 CA023100] Funding Source: Medline
- NICHD NIH HHS [U54 HD012303, R01 HD047400] Funding Source: Medline
- BLRD VA [I01 BX000130] Funding Source: Medline
In myotonic dystrophy (DM1), both inactivation of muscleblind proteins and increased levels of CUG-BP1 are reported. These events have been shown to contribute independently to aberrant splicing of a subset RNAs. We demonstrate that steady-state levels of the splice regulator, hnRNP H, are elevated in DM1 myoblasts and that increased hnRNP H levels in normal myoblasts results in the inhibition of insulin receptor (IR) exon 11 splicing in a manner similar to that observed in DM1. In normal myoblasts, overexpression of either hnRNP H or CUG-BP1 results in the formation of an RNA-dependent suppressor complex consisting of both hnRNP H and CUG-BP1, which is required to maximally inhibit IR exon 11 inclusion. Elevated levels of MBNL1 show RNA-independent interaction with hnRNP H and dampen the inhibitory activity of increased hnRNP H levels on IR splicing in normal myoblasts. In DM1 myoblasts, overexpression of MBNL1 in conjunction with si-RNA mediated depletion of hnRNP H contributes to partial rescue of the IR splicing defect. These data demonstrate that coordinated physical and functional interactions between hnRNP H, CUG-BP1 and MBNL1 dictate IR splicing in normal and DM1 myoblasts.
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