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Molecular and Cellular Biology, May 2007, p. 3290-3302, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.02289-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Xinjun Ji,1 Jian Kong,1 Russ P. Carstens,2 and Stephen A. Liebhaber1*

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 {alpha}-globin mRNA is bound at a C-rich motif in the 3' untranslated region (3'UTR) by the KH domain protein {alpha}-globin poly(C)-binding protein ({alpha}CP). This "{alpha}-complex" is essential to cytoplasmic stability of {alpha}-globin mRNA in erythroid cells. Here we report that the 3'UTR {alpha}-complex also serves an independent nuclear role as a splice enhancer. Consistent with this role, we find that {alpha}CP binds {alpha}-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 {alpha}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 {alpha}CP complex may serve to "prepackage" {alpha}-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.

* Corresponding author. Mailing address: Departments of Genetics and Medicine, University of Pennsylvania School of Medicine, Room 428 CRB, 415 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-7834. Fax: (215) 573-5157. E-mail: liebhabe{at}mail.med.upenn.edu

{triangledown} Published ahead of print on 26 February 2007.

Molecular and Cellular Biology, May 2007, p. 3290-3302, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.02289-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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