Published online September 10, 2007
doi:10.1083/jcb.200706048
The Journal of Cell Biology, Vol. 178, No. 6, 951-964
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Smith et al.
Defining early steps in mRNA transport: mutant mRNA in myotonic dystrophy type I is blocked at entry into SC-35 domains
Kelly P. Smith,
Meg Byron,
Carol Johnson,
Yigong Xing, and
Jeanne B. Lawrence
Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655
Correspondence to Jeanne B. Lawrence: jeanne.lawrence{at}umassmed.edu
In myotonic dystrophy type 1 (DM1), triplet repeat expansion in the 3' untranslated region of dystrophia myotonica protein kinase (DMPK) causes the nuclear retention of mutant messenger RNA (mRNA). Although the DMPK gene locus positions precisely at the outer edge of a factor-rich SC-35 domain, the normal mRNA consistently accumulates within the domain, and this RNA is depleted upon transcriptional inhibition. In DM1, mutant transcripts detach from the gene but accumulate in granules that abut but do not enter SC-35 domains, suggesting that RNA entry into the domain is blocked. Despite their exclusion from these compartments, mutant transcripts are spliced. MBNL1 (muscleblind-like protein 1) is an alternative splicing factor that becomes highly concentrated with mutant RNA foci. Small interfering RNA–mediated knockdown of MBNL1 promotes the accumulation or entry of newly synthesized mutant transcripts in the SC-35 domain. Collectively, these data suggest that an initial step in the intranuclear path of some mRNAs is passage from the gene into an SC-35 domain and implicate these structures in postsplicing steps before export.
Abbreviations used in this paper: DMPK, dystrophia myotonica protein kinase; hnRNP H, heterogeneous nuclear RNP H; HSMM, human skeletal muscle myoblast; MRG, mutant RNA granule.
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