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

Star-PAP is a non-canonical poly(A) polymerase that selects mRNA targets for polyadenylation. Yet, genome-wide direct Star-PAP targets or the mechanism of specific mRNA recognition is still vague. Here, we employ HITS-CLIP to map the cellular Star-PAP binding landscape and the mechanism of global Star-PAP mRNA association. We show a transcriptome-wide association of Star-PAP that is diminished on Star-PAP depletion. Consistent with its role in the 3′-UTR processing, we observed a high association of Star-PAP at the 3′-UTR region. Strikingly, there is an enrichment of Star-PAP at the coding region exons (CDS) in 42% of target mRNAs. We demonstrate that Star-PAP binding de-stabilises these mRNAs indicating a new role of Star-PAP in mRNA metabolism. Comparison with earlier microarray data reveals that while UTR-associated transcripts are down-regulated, CDS-associated mRNAs are largely up-regulated on Star-PAP depletion. Strikingly, the knockdown of a Star-PAP coregulator RBM10 resulted in a global loss of Star-PAP association on target mRNAs. Consistently, RBM10 depletion compromises 3′-end processing of a set of Star-PAP target mRNAs, while regulating stability/turnover of a different set of mRNAs. Our results establish a global profile of Star-PAP mRNA association and a novel role of Star-PAP in the mRNA metabolism that requires RBM10-mRNA association in the cell.