Alternative polyadenylation: An enigma of transcript length variation in health and disease

Abstract

Alternative polyadenylation (APA) is a molecular mechanism during a pre‐mRNA processing that involves usage of more than one polyadenylation site (PA‐site) generating transcripts of varying length from a single gene. The location of a PA‐site affects transcript length and coding potential of an mRNA contributing to both mRNA and protein diversification. This variation in the transcript length affects mRNA stability and translation, mRNA subcellular and tissue localization, and protein function. APA is now considered as an important regulatory mechanism in the pathophysiology of human diseases. An important consequence of the changes in the length of 3′‐untranslated region (UTR) from disease‐induced APA is altered protein expression. Yet, the relationship between 3′‐UTR length and protein expression remains a paradox in a majority of diseases. Here, we review occurrence of APA, mechanism of PA‐site selection, and consequences of transcript length variation in different diseases. Emerging evidence reveals coordinated involvement of core RNA processing factors including poly(A) polymerases in the PA‐site selection in diseases‐associated APAs. Targeting such APA regulators will be therapeutically significant in combating drug resistance in cancer and other complex diseases. This article is categorized under: RNA Processing > 3′ End Processing RNA in Disease and Development > RNA in Disease Translation > Regulation

Reprogramming RNA processing: an emerging therapeutic landscape

“…role in post-transcriptional gene regulation (Figure 1B) [1]. Specific APA events have been implicated in several pathologies ranging from neurodegenerative to autoimmune disorders [120] (Figure 2C). Interestingly, global patterns of APA-dependent isoform expression have also been observed in a variety of malignancies, with a general trend toward transcripts harboring shortened 3′UTRs [121][122][123].…”

The Cap-Binding Complex CBC and the Eukaryotic Translation Factor eIF4E: Co-Conspirators in Cap-Dependent RNA Maturation and Translation

“…In this way, RNA metabolism provides a means to reprogram the transcriptional signals which are the ultimate substrates of the ribosomes. For instance, splice variants and alternatively polyadenylated transcript variants can produce proteins with opposing or modified functions [ 1 , 2 ]. Elevated RNA nuclear export can increase the availability of transcripts to the translation machinery, bypassing the need to increase transcription [ 3 ].…”

“…Alternative polyadenylation (APA) is defined as the cleavage of alternative PASs within the 3′UTR, introns, or coding region of transcripts; altered PAS cleavage efficiency; and/or alterations in poly(A) tail length [ 75 , 76 , 77 ]. APA can affect RNA stability, export, localization, translation, and in some cases, the functionality of the protein product by altering the coding sequence, such as by generating truncated proteins with alternative C-terminal domains [ 2 ]. The impact of APA on gene expression is highlighted by the observation that at least 70% of mammalian RNAs express APA isoforms [ 77 ].…”

Developmentally regulated alternate 3’ end cleavage of nascent transcripts controls dynamic changes in protein expression in an adult stem cell lineage

“…In particular, the selection of alternative sites at which to make the 3’end cut that terminates the nascent transcript (termed alternative polyadenylation – APA) leads to expression of mRNA isoforms with different 3’UTR lengths (Di Giammartino et al 2011; Shi 2012; Mueller et al 2013). APA has been associated with specific cell types or disease states (Ji et al 2009; Ji and Tian 2009; Mayr and Bartel 2009; Elkon et al 2012; Morris et al 2012; Gruber and Zavolan 2019; Mohanan et al 2021).…”