3'UTR Diversity: Expanding Repertoire of RNA Alterations in Human mRNAs

Abstract

Genomic information stored in the DNA is transcribed to the mRNA and translated to proteins. The 3' untranslated regions (3'UTRs) of the mRNA serve pivotal roles in posttranscriptional gene expression, regulating mRNA stability, translation, and localization. Similar to DNA mutations producing aberrant proteins, RNA alterations expand the transcriptome landscape and change the cellular proteome. Recent global analyses reveal that many genes express various forms of altered RNAs, including 3'UTR length variants. Alternative polyadenylation and alternative splicing are involved in diversifying 3'UTRs, which could act as a hidden layer of eukaryotic gene expression control. In this review, we summarize the functions and regulations of 3'UTRs and elaborate on the generation and functional consequences of 3'UTR diversity. Given that dynamic 3'UTR length control contributes to phenotypic complexity, dysregulated 3'UTR diversity might be relevant to disease development, including cancers. Thus, 3'UTR diversity in cancer could open exciting new research areas and provide avenues for novel cancer theragnostics.

Keywords: 3′UTR diversity; RNA alterations; alternative polyadenylation; alternative splicing; cancer; transcriptome.

Fig. 1. Length and internal introns in untranslated region (UTR) during evolution.

The average length of the 5′UTR and 3′UTR of mRNA among different organisms. The 5′UTR is typically shorter compared to the 3′UTR. In Homo sapiens, the average length of the 3′UTR is about 1030 nucleotides (nt), which is longer than the average length of the 3′UTR in other species. Percentage of genes containing internal introns is also shown in H. sapiens (8%) and other mammals (2%).

Fig. 2. Roles of 3′ untranslated region (3′UTR) in post-transcriptional regulation..

The diagram illustrates a typical mRNA structure consisting of 5′UTR, coding region, and 3′UTR. The 3′UTR is located following the stop codon and before the poly(A) tail. It includes cisregulatory elements like AU-rich elements (AREs), Alu elements and microRNA (miRNA) targets, and polyadenylation sites. The 3′UTRs play important roles in post-transcriptional gene regulation of mRNA stability, translation, and localization.

Fig. 3. Regulatory events generating 3′ untranslated region (3′UTR) length diversity.

(A) Alternative polyadenylation (APA) in 3′UTR. The generation of 3′UTR length diversity using different cleavage and polyadenylation sites: proximal polyadenylation site (pPAS) and distal polyadenylation site (dPAS). The selection of pPAS over dPAS, or vice versa, can result in different 3′UTR lengths. If the pPAS is selected, the 3′UTR will be shorter (shown in the pink box); the dPAS is selected, the 3′UTR will be longer (shown in the pink box and red box). (B) Alternative splicing (AS) within 3′UTR. The generation of 3′UTR length diversity using the internal intron in 3′UTR (shown in the blue line). Inclusion or skipping of this intron can affect the length of the 3′UTR. If the intron is included, 3′UTR will contain an intronic sequence (shown in the blue box). (C) Combination of APA and AS events in 3′UTR. More 3'UTR variants can be generated.