Abstract
Apolipoprotein B (apoB) mRNA editing involves site-specific deamination of cytidine to form uridine, resulting in the production of an in-frame stop codon. Protein translated from edited mRNA is associated with a reduced risk of atherosclerosis, and hence the protein factors that regulate hepatic apoB mRNA editing are of interest. A human protein essential for apoB mRNA editing and an eight-amino acid-longer variant of no known function have been recently cloned. We report that both proteins, henceforth referred to as ACF64 and ACF65, supported APOBEC-1 (the catalytic subunit of the editosome) equivalently in editing of apoB mRNA. They are encoded by a single 82-kb gene on chromosome 10. The transcripts are encoded by 15 exons that are expressed from a tissue-specific promoter minimally contained within the -0.33-kb DNA sequence. ACF64 and ACF65 mRNAs are expressed in both liver and intestinal cells in an approximate 1:4 ratio. Exon 11 is alternatively spliced to include or exclude 24 nucleotides of exon 12, thereby encoding ACF65 and ACF64, respectively. Recognition motifs for the serine/arginine-rich (SR) proteins SC35, SRp40, SRp55, and SF2/ASF involved in alternative RNA splicing were predicted in exon 12. Overexpression of these SR proteins in liver cells demonstrated that alternative splicing of a minigene-derived transcript to express ACF65 was enhanced 6-fold by SRp40. The data account for the expression of two editing factors and provide a possible explanation for their different levels of expression.
Highlights
Mammalian mRNAs can be post-transcriptionally modified by site-specific adenosine or cytidine deaminases in a process known as mRNA editing [1]
A human protein essential for Apolipoprotein B (apoB) mRNA editing and an eight-amino acid-longer variant of no known function have been recently cloned. We report that both proteins, referred to as ACF64 and ACF65, supported APOBEC-1 equivalently in editing of apoB mRNA
The complexity of the editosome may be attributed to several identified proteins that associated with APOBEC-1 and/or the apoB mRNA editing site to modulate the efficiency of apoB mRNA editing (10 –16)
Summary
Mammalian mRNAs can be post-transcriptionally modified by site-specific adenosine or cytidine deaminases in a process known as mRNA editing [1]. Adenosine deamination is catalyzed by a family of enzymes known as ADARs (adenosine deaminases active on RNA) that recognize select adenosines within double-stranded regions of substrate mRNAs and convert them to inosine [2]. Editing of cytidine by deamination is catalyzed by enzymes known as CDARs (cytidine deaminases active on RNA) and results in a change to uridine. The complexity of the editosome may be attributed to several identified proteins that associated with APOBEC-1 and/or the apoB mRNA editing site to modulate the efficiency of apoB mRNA editing (10 –16). The interactions, functions, and regulation of the auxiliary proteins are of interest in the study of the mechanism of apoB mRNA editing and because apoB mRNA editing is a regulated process during tissue development [17] and in response to metabolic or hormonal perturbation [18, 19]. A promoter region was identified immediately upstream of exon 1, and several ESTs were identified that suggested that the ACF transcript may be subject to further alternative and nonexclusive alternative splicing events
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