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

WIREs RNA   27 September 2021| https://doi.org/10.1002/wrna.1692 

Neeraja K. Mohanan, Feba Shaji, Ganesh R. Koshre, Rakesh S. Laishram

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.

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