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  • The EMBO Journal (2006) 25, 4271 - 4283
  • doi:10.1038/sj.emboj.7601296

Published online: 31 August 2006

Interaction of musleblind, CUG-BP1 and hnRNP H proteins in DM1-associated aberrant IR splicing

Sharan Paul1, Warunee Dansithong1, Dongho Kim2, John Rossi2, Nicholas JG Webster3, Lucio Comai1 and Sita Reddy1

  1. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  2. Division of Molecular Biology, City of Hope, Duarte, CA, USA
  3. Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA, USA

Correspondence to:

Sita Reddy, Institute for Genetic Medicine (IGM), Keck School of Medicine, University of Southern California, Room 240, 2250 Alcazar Street, Los Angeles, CA 90033, USA. Tel.: +1 323 442 2457/3950; Fax: +1 323 442 2764; E-mails: E-mail: sitaredd@usc.edu

Lucio Comai, Institute for Genetic Medicine (IGM), Keck School of Medicine, University of Southern California, Room 240, 2250 Alcazar Street, Los Angeles, CA 90033, USA. Tel.: +1 323 442 2457/3950; Fax: +1 323 442 2764; E-mail: comai@usc.edu

Received 28 February 2006; Accepted 25 July 2006

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.

  • Keywords:

    • CUG-BP1,
    • hnRNP H,
    • muscleblind,
    • myotonic dystrophy 1,
    • splicing