Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
EMBO J. 2011 May 27;30(13):2622-33. doi: 10.1038/emboj.2011.171.
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.
转录后调控对于基因调控至关重要。这些调控通常基于反式作用蛋白与靶 RNA 上顺式作用基序的序列特异性结合。先前的研究表明，KH 结构域蛋白 αCP 与 hα-珠蛋白 mRNA 的 3'UTR C 丰富基序结合，并有助于其细胞质稳定性。在这里，我们报告说，这个 3'UTR αCP 复合物通过增强 hα-珠蛋白转录本的 3'加工来调节成熟 α-珠蛋白 mRNA 的产生。我们接着证明，这种核活性反映了切割和多聚腺苷酸化反应的增强，并且 αCP 在体内与 3'加工复合物的核心成分相互作用。与它的核加工活性一致，我们的研究表明，αCP 在 hα-珠蛋白染色质基因座上共转录组装，并且这种加载在基因的 3'末端选择性富集。通过一个共同的 RNA-蛋白质复合物将核加工与细胞质稳定联系起来，为整合对目标 mRNA 进行稳健和持续表达至关重要的连续控制奠定了基础。
