Alternative Polyadenylation of mRNAs: 3'-Untranslated Region Matters in Gene Expression

Abstract

Almost all of eukaryotic mRNAs are subjected to polyadenylation during mRNA processing. Recent discoveries showed that many of these mRNAs contain more than one polyadenylation sites in their 3' untranslated regions (UTR) and that alternative polyadenylation (APA) is prevalent among these genes. Many biological processes such as differentiation, proliferation, and tumorigenesis have been correlated to global APA events in the 3' UTR of mRNAs, suggesting that these APA events are tightly regulated and may play important physiological roles. In this review, recent discoveries in the physiological roles of APA events, as well as the known and proposed mechanisms are summarized. Perspective for future directions is also discussed.

Keywords: 3′ UTR; 3′-end processing; alternative polyadenylation; mTOR; post-transcriptional gene regulation.

Fig. 1.

(A) 3′ end processing machinery assembly at poly(A) site. The endonucleolytic cleavage at poly(A) site is mediated by the binding of 3′ end processing factors including multi-subunit protein complexes CPSF, CSFT, CFI, and CFII to the USE-PAS-DSE sequence elements. (B) Schematic illustration of UTR-APA and CR-APA of mRNA. Exons are represented by rectangular squares with coding DNA sequences being thicker than UTRs. Introns are represented by thin lines. For UTR-APA, alternative PAS resides in 3′ UTR. Therefore, UTR-APA can generate transcripts with varying UTR lengths without changing the coding sequences. There are two major types of CR-APA, as illustrated. Both types of CR-APA may yield transcripts with truncated coding sequences.

Fig. 2.

mTORC1 activation mediates global 3′ UTR shortening in the transcriptome. Genes belonging to the ubiquitin-mediated proteolysis pathway are shown to be preferentially targeted by mTOR-mediated 3′ UTR shortening.