Abstract
Post-transcriptional controls are critical to gene regulation. These controls are frequently based on sequence-specific binding of trans-acting proteins to cis-acting motifs on target RNAs. Prior studies have revealed that the KH-domain protein, αCP, binds to a 3' UTR C-rich motif of hα-globin mRNA and contributes to its cytoplasmic stability. Here, we report that this 3' UTR αCP complex regulates the production of mature α-globin mRNA by enhancing 3' processing of the hα-globin transcript. We go on to demonstrate that this nuclear activity reflects enhancement of both the cleavage and the polyadenylation reactions and that αCP interacts in vivo with core components of the 3' processing complex. Consistent with its nuclear processing activity, our studies reveal that αCP assembles co-transcriptionally at the hα-globin chromatin locus and that this loading is selectively enriched at the 3' terminus of the gene. The demonstrated linkage of nuclear processing with cytoplasmic stabilization via a common RNA-protein complex establishes a basis for integration of sequential controls critical to robust and sustained expression of a target mRNA.