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J. Biol. Chem., Vol. 279, Issue 1, 197-206, January 2, 2004

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Identification of Novel Alternative Splice Variants of APOBEC-1 Complementation Factor with Different Capacities to Support Apolipoprotein B mRNA Editing^*

Mark P. Sowden, David M. Lehmann¶||, Xiaoyan Lin, Charles O. Smith**, and Harold C. Smith¶

From the Department of Biochemistry and Biophysics, the Department of Pathology and Laboratory Medicine, and the ^¶Environmental Health Sciences and James P. Wilmot Cancer Centers, University of Rochester, Rochester, New York 14642

Two novel mRNA transcripts have been identified that result from species- and tissue-specific, alternative polyadenylation and splicing of the pre-mRNA encoding the apolipoprotein B (apoB) editing catalytic subunit 1 (APOBEC-1) complementation factor (ACF) family of related proteins. The alternatively processed mRNAs encode 43- and 45-kDa proteins that are components of the previously identified p44 cluster of apoB RNA binding, editosomal proteins. Recombinant ACF45 displaced ACF64 and ACF43 in mooring sequence RNA binding but did not demonstrate strong binding to APOBEC-1. In contrast, ACF43 bound strongly to APOBEC-1 but demonstrated weak binding to mooring sequence RNA. Consequently ACF45/43 complemented APOBEC-1 in apoB mRNA editing with less efficiency than full-length ACF64. These data, together with the finding that all ACF variants were co-expressed in rat liver nuclei (the site of apoB mRNA editing), suggested that ACF variants might compete with one another for APOBEC-1 and apoB mRNA binding and thereby contribute to the regulation of apoB mRNA editing. In support for this hypothesis, the ratio of nuclear ACF65/64 to ACF45/43 decreased when hepatic editing was inhibited by fasting and increased when editing was re-stimulated by refeeding. These findings suggested a new model for the regulation of apoB mRNA editing in which the catalytic potential of editosomes is modulated at the level of their assembly by alterations in the relative abundance of multiple related RNA-binding auxiliary proteins and the expression level of APOBEC-1.

Received for publication, July 21, 2003 , and in revised form, October 6, 2003.

^* This work was supported in part by Public Health Services Grant DK43739, a grant from the Alcoholic Beverage Medical Research Foundation (to H. C. S.), and a Department of Defense, Air Force grant (to H. C. S. and M. P. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF442133–AF442135.

^|| Supported by United States Public Health Service Toxicology Training Grant 5T32 ES07026.

^** Current address: School of Arts and Sciences, Cornell University, Ithaca, NY 14853.

To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, University of Rochester, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-275-4267; Fax: 585-275-6007; E-mail: harold_smith{at}urmc.rochester.edu.

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