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The 3' Untranslated Region Complex Involved in Stabilization of Human -globin mRNA Assembles in the Nucleus and Serves an Independent Role as a Splice Enhancer

Departments of Genetics and Medicine,¹ Department of Medicine, Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104²

Received 30 November 2005/ Returned for modification 27 December 2005/ Accepted 8 February 2007

Posttranscriptional controls, mediated primarily by RNA-protein complexes, have the potential to alter multiple steps in RNA processing and function. Human -globin mRNA is bound at a C-rich motif in the 3' untranslated region (3'UTR) by the KH domain protein -globin poly(C)-binding protein (CP). This "-complex" is essential to cytoplasmic stability of -globin mRNA in erythroid cells. Here we report that the 3'UTR -complex also serves an independent nuclear role as a splice enhancer. Consistent with this role, we find that CP binds -globin transcripts prior to splicing. Surprisingly, this binding occurs at C-rich sites within intron I as well as at the 3'UTR C-rich determinant. The intronic and 3'UTR CP complexes appear to have distinct effects on splicing. While intron I complexes repress intron I excision, the 3'UTR complex enhances splicing of the full-length transcript both in vivo and in vitro. In addition to its importance to splicing, nuclear assembly of the 3'UTR CP complex may serve to "prepackage" -globin mRNA with its stabilizing complex prior to cytoplasmic export. Linking nuclear and cytoplasmic controls by the action of a particular RNA-binding protein, as reported here, may represent a modality of general importance in eukaryotic gene regulation.

Published ahead of print on 26 February 2007.

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