Evolution and Biological Roles of Alternative 3'UTRs

Abstract

More than half of human genes use alternative cleavage and polyadenylation to generate alternative 3' untranslated region (3'UTR) isoforms. Most efforts have focused on transcriptome-wide mapping of alternative 3'UTRs and on the question of how 3'UTR isoform ratios may be regulated. However, it remains less clear why alternative 3'UTRs have evolved and what biological roles they play. This review summarizes our current knowledge of the functional roles of alternative 3'UTRs, including mRNA localization, mRNA stability, and translational efficiency. Recent work suggests that alternative 3'UTRs may also enable the formation of protein-protein interactions to regulate protein localization or to diversify protein functions. These recent findings open an exciting research direction for the investigation of new biological roles of alternative 3'UTRs.

Keywords: 3′UTR; RNA granule; RNA-binding protein; alternative polyadenylation; diversification of protein functions; multifunctionality; noncoding RNA; post-transcriptional gene regulation; protein abundance; protein localization; protein–protein interactions.

Figure 1. 3′UTR length of ubiquitously transcribed or tissue-restricted genes

A. Single-UTR genes. Here, ubiquitously expressed genes are defined to be expressed in at least six out of seven human tissues, including testis, ovary, embryonic stem (ES) cells, B cells, muscle, breast and brain. N, Number of genes in each category. B. Multi-UTR genes. As in (A).

Figure 2. Diverse biological roles of alternative 3′UTRs

A. Regulation of mRNA localization. The long 3′UTR contains a cis-element that is recognized by an RBP (light blue). Interaction with a molecular motor (dark blue) enables directional movement along actin fibers (red) and results in localization of the long 3′UTR isoform to the dendrites of neurons. The short 3′UTR isoforms lack the cis-acting element and remain localized to the soma. AA indicates a poly(A) tail. B. Activity-dependent regulation of translation of alternative 3′UTR isoforms. In the resting state (left) the short 3′UTR isoform of BDNF is translated which results in BDNF protein expression in the soma. After membrane depolarization by synaptic activation (right) the long 3′UTR isoform is translated which results in BDNF protein expression in dendrites and synapses. C. Cell-type specific regulation of protein abundance through interplay of alternative 3′UTRs with miRNAs. Presence of the miRNA and predominant expression of long 3′UTR isoforms in one cell type results in low protein output, whereas predominant expression of short 3′UTR isoforms results in escape from miRNA regulation and leads to high protein output. AA indicates a poly(A) tail. D. Alternative 3′UTRs use the scaffold function to regulate 3′UTR-dependent membrane protein localization. HuR-mediated recruitment of SET by the long 3′UTR facilitates formation of a protein complex containing SET/RAC1/CD47, which enables plasma membrane localization. E. Alternative 3′UTRs mediate protein-protein interactions to regulate protein function. Long 3′UTRs bind RBPs, which may be able to recruit effector proteins of diverse functions. Effector proteins may act as chaperones to achieve alternative protein folds or as enzymes that add alternative post-translational modifications. Or, by mediating protein-protein interactions, they may enable the formation of alternative protein complexes. F. Phenotypic diversity of single cells through variability in alternative 3′UTR isoform expression. Each cell of a clonal population expresses varying amounts of alternative 3′UTR isoforms which may contribute to differences in protein expression and phenotypic diversity among the population. AA indicates a poly(A) tail.