Alternative polyadenylation: new insights from global analyses

Abstract

Recent studies have revealed widespread mRNA alternative polyadenylation (APA) in eukaryotes and its dynamic spatial and temporal regulation. APA not only generates proteomic and functional diversity, but also plays important roles in regulating gene expression. Global deregulation of APA has been demonstrated in a variety of human diseases. Recent exciting advances in the field have been made possible in a large part by high throughput analyses using newly developed experimental tools. Here I review the recent progress in global studies of APA and the insights that have emerged from these and other studies that use more conventional methods.

FIGURE 1.

Classification of mRNA alternative polyadenylation. Exons are shown as boxes and introns as lines. The arrows point to the 3′ end of the transcript. For splicing events, the 5′ and 3′ splice sites are connected by dotted lines. Positions of the alternative poly(A) sites (PASs) are marked. Distinct terminal exons are colored in red or green and the composite exons are shown in red and orange.

FIGURE 2.

Conserved poly(A) site sequence features and arrangement. (A) Conserved poly(A) site sequence features. U-rich sequences are shown in blue, A-rich sequences in red, UA-rich sequences in pink. Nucleotide positions relative to the cleavage site are labeled. (USE) Upstream sequence element; (ARE) A-rich element; (DSE) downstream sequence element. (B) Conserved arrangement of poly(A) sites. The arrows point to the 3′ end of the transcript. The most distal PAS has strong canonical features and is shown as a blue and red box, similar to A. The proximal PAS tend to diverge from canonical PAS features and are shown as light blue boxes.

FIGURE 3.

Regulatory mechanisms for poly(A) site selection. (A) Depiction of the mRNA 3′ processing reaction and the reaction rate formula. k is the reaction constant. [X]: Concentration of X. PAS is the poly(A) site-containing pre-mRNA. See text for details. (B–E) Regulatory mechanisms for poly(A) site selection. Poly(A) sites (PAS) are shown as rectangular boxes. Core 3′ processing factors are shown as orange boxes. The directionality of the mRNAs is marked with arrows. In B and E, the strengths of the alternative PAS are labeled. Strong PAS are shown as dark blue boxes and weak PAS as light blue boxes.