Alternative Polyadenylation: a new frontier in post transcriptional regulation

Abstract

Polyadenylation of pre-messenger RNA (pre-mRNA) specific sites and termination of their downstream transcriptions are signaled by unique sequence motif structures such as AAUAAA and its auxiliary elements. Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism that processes RNA products depending on its 3'-untranslated region (3'-UTR) specific sequence signal. APA processing can generate several mRNA isoforms from a single gene, which may have different biological functions on their target gene. As a result, cellular genomic stability, proliferation capability, and transformation feasibility could all be affected. Furthermore, APA modulation regulates disease initiation and progression. APA status could potentially act as a biomarker for disease diagnosis, severity stratification, and prognosis forecast. While the advance of modern throughout technologies, such as next generation-sequencing (NGS) and single-cell sequencing techniques, have enriched our knowledge about APA, much of APA biological process is unknown and pending for further investigation. Herein, we review the current knowledge on APA and how its regulatory complex factors (CFI/IIm, CPSF, CSTF, and RBPs) work together to determine RNA splicing location, cell cycle velocity, microRNA processing, and oncogenesis regulation. We also discuss various APA experiment strategies and the future direction of APA research.

Fig. 1

Comparison of APA and AS. a-c The patterns of APA can be classified into two main types: UTR-APA and CR-APA. For UTR-APA, alternative PAS resides in the 3′-UTR. Therefore, UTR-APA can generate transcripts with varying UTR lengths without changing the coding sequences. There are major types of CR-APA that may yield transcripts with truncated coding sequence. d Yellow is used to label the extended exon. For AS, e-constitutive splicing; f exon skipping/ inclusion;g alternative 5′-splice sites;h alternative 3′-splice sites; i intron retention; j mutually exclusive exons

Fig. 2

The APA complex and its machinery. CFIm complex binds to the conserved upstream UGUA region to mediate the cleavage reaction and recruit other proteins, including CPSF and CSTF. After combining with PAP, this complex translocates through the pre-mRNA in a 5′ to 3′ fashion. Upon arrival at the AAUAAA region, the adenosine acidification signal CPSF recognizes the polyadenylation signal AAUAAA and CPSF73 cleaves the mRNA. CSTF then binds to the GU- or U-rich sequence. The U-rich region bound to the FIP1L1 subunit of the CPSF is located between the polyadenylation signal AAUAAA and the cleavage site. Symplekin functions as a scaffold protein and PAPs catalyze the addition of untemplated adenosines. Generally, the usage of the proximal pAs generates short isoforms and the translation can be suppressed, often resulting in less protein

Fig. 3

Track of PIGN by Grch37/hg19. PIGN location in chromosome18(q21.33) has three transcripts. There are 6 pAs in the polyA database

Fig. 4

APA Impacts at molecular, cellular, and clinical levels. a APA can affect cell functions through various molecular mechanisms;b&c APA has relationship with many type diseases and the diagnosis, prognosis and treatment of diseases