Published online 15 July 2005
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HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence
Department of Molecular Biology, Beckman Research Institute of the City of Hope Duarte, CA, USA 1Department of Human Genetics, CHUQ, Pavillon CHUL and Laval University Quebec City, Canada 2Department of Biology, Beckman Research Institute of the City of Hope Duarte, CA, USA
*To whom correspondence should be addressed. Tel: +1 626 301 8360; Fax: +1 626 301 8271; Email: jrossi{at}coh.org
Received February 17, 2005. Revised June 22, 2005. Accepted June 22, 2005.
Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder associated with a (CUG)n expansion in the 3'-untranslated region of the DMPK (DM1 protein kinase) gene. Mutant DMPK mRNAs containing the trinucleotide expansion are retained in the nucleus of DM1 cells and form discrete foci. The nuclear sequestration of RNA binding proteins and associated factors binding to the CUG expansions is believed to be responsible for several of the splicing defects observed in DM1 patients and could ultimately be linked to DM1 muscular pathogenesis. Several RNA binding proteins capable of co-localizing with the nuclear-retained mutant DMPK mRNAs have already been identified but none can account for the nuclear retention of the mutant transcripts. Here, we have employed a modified UV crosslinking assay to isolate proteins bound to mutant DMPK-derived RNA and have identified hnRNP H as an abundant candidate. The specific binding of hnRNP H requires not only a CUG repeat expansion but also a splicing branch point distal to the repeats. Suppression of hnRNP H expression by RNAi rescued nuclear retention of RNA with CUG repeat expansions. The identification of hnRNP H as a factor capable of binding and possibly modulating nuclear retention of mutant DMPK mRNA may prove to be an important link in our understanding of the molecular mechanisms that lead to DM1 pathogenesis.
Present addresses: Marc-Andre Langlois, MRC Laboratory of Molecular Biology, Hills Road, Cambridge, UK
Kwang-Back Lee, School of Dental Science, UCLA, Los Angeles, CA, USA
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