Alternative polyadenylation (APA) is a widespread mechanism of gene regulation that generates distinct 3′ ends in transcripts made by RNA polymerase II.
APA is tissue specific and globally regulated in various conditions, such as cell proliferation and differentiation, and in response to extracellular cues.
APA occurring in 3′ untranslated regions (3′ UTRs) leads to the production of mRNA isoforms with different metabolisms and can also affect protein localization.
APA occurring in the region upstream of the 3′ UTR is often coupled with splicing and can lead to the production of distinct protein isoforms. It can also function by repressing gene expression.
APA is regulated by several known mechanisms, including regulation of the levels of core RNA-processing factors and other RNA-binding proteins, as well as by splicing and transcriptional dynamics.
Alternative polyadenylation (APA) is an RNA-processing mechanism that generates distinct 3′ termini on mRNAs and other RNA polymerase II transcripts. It is widespread across all eukaryotic species and is recognized as a major mechanism of gene regulation. APA exhibits tissue specificity and is important for cell proliferation and differentiation. In this Review, we discuss the roles of APA in diverse cellular processes, including mRNA metabolism, protein diversification and protein localization, and more generally in gene regulation. We also discuss the molecular mechanisms underlying APA, such as variation in the concentration of core processing factors and RNA-binding proteins, as well as transcription-based regulation.
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The authors thank members of their laboratories for helpful discussions, and I. Boluck for assistance with manuscript preparation. Work in the authors' laboratories was funded by grants GM84089 (B.T.), and GM28983 and GM118136 (J.L.M.) from the US National Institutes of Health.
The authors declare no competing financial interests.
- PUF protein
(Pumilio and FBF homology family protein). A member of a family of RNA-binding proteins that regulate aspects of mRNA metabolism by binding to specific sequences in 3′ untranslated regions.
- STAU1-mediated mRNA decay
An mRNA decay mechanism in which RNA structures in the 3′ untranslated region interact with double-stranded RNA-binding protein Staufen homologue 1 (STAU1) to mediate mRNA decay.
- AU-rich element-mediated decay
mRNA decay elicited by the presence of AU-rich elements (AREs) in the 3′ untranslated region.
- PIWI-interacting RNAs
Small non-coding RNAs that form RNA–protein complexes with PIWI proteins to silence transposable elements in germline cells of metazoans.
- Non-stop decay
An mRNA decay mechanism that specifically degrades mRNAs without a stop codon.
A nuclear or cytoplasmic multiprotein complex that degrades mRNAs through the activity of 3′-to-5′ exoribonucleases.
- Non-canonical PAPs
(Non-canonical poly(A) polymerases). Enzymes that have distinct structural features and are capable of synthesizing poly(A) tails but are not typically associated with the polyadenylation machinery.
- Paused Pol II
(Paused RNA polymerase II). Pol II that has paused in the promoter-proximal region of the mRNA and is poised for productive elongation.
A dynamic nuclear compartment composed of RNA-binding proteins and RNAs. The functions of paraspeckles are not entirely clear.
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Tian, B., Manley, J. Alternative polyadenylation of mRNA precursors. Nat Rev Mol Cell Biol 18, 18–30 (2017). https://doi.org/10.1038/nrm.2016.116
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