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Context-specific regulation and function of mRNA alternative polyadenylation

Nature Reviews Molecular Cell Biology volume 23, pages 779–796 (2022)Cite this article

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Abstract

Alternative cleavage and polyadenylation (APA) is a widespread mechanism to generate mRNA isoforms with alternative 3′ untranslated regions (UTRs). The expression of alternative 3′ UTR isoforms is highly cell type specific and is further controlled in a gene-specific manner by environmental cues. In this Review, we discuss how the dynamic, fine-grained regulation of APA is accomplished by several mechanisms, including cis-regulatory elements in RNA and DNA and factors that control transcription, pre-mRNA cleavage and post-transcriptional processes. Furthermore, signalling pathways modulate the activity of these factors and integrate APA into gene regulatory programmes. Dysregulation of APA can reprogramme the outcome of signalling pathways and thus can control cellular responses to environmental changes. In addition to the regulation of protein abundance, APA has emerged as a major regulator of mRNA localization and the spatial organization of protein synthesis. This role enables the regulation of protein function through the addition of post-translational modifications or the formation of protein–protein interactions. We further discuss recent transformative advances in single-cell RNA sequencing and CRISPR–Cas technologies, which enable the mapping and functional characterization of alternative 3′ UTRs in any biological context. Finally, we discuss new APA-based RNA therapeutics, including compounds that target APA in cancer and therapeutic genome editing of degenerative diseases.

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Fig. 1: Cleavage and polyadenylation of mRNA isoforms at their 3′ ends.
Fig. 2: Overview of regulation of alternative polyadenylation by co-transcriptional and post-transcriptional mechanisms.
Fig. 3: Co-transcriptional regulators of alternative polyadenylation.
Fig. 4: Gene-specific regulation of alternative 3′ UTR isoforms.
Fig. 5: Cell-type-specific regulation of single-UTR and multi-UTR genes is accomplished by different regulatory modes.
Fig. 6: Examples of functions of alternative 3′ UTRs.
Fig. 7: Manipulation of alternative 3′ UTR expression.

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Acknowledgements

The authors thank all members of the Mayr laboratory for helpful discussions and critical reading of the manuscript. This work was funded by the NIH Director′s Pioneer Award (DP1-GM123454), a grant from the G. Herold and Leila Y. Mathers Foundation, the Pershing Square Sohn Cancer Research Alliance and an NCI Cancer Center Support Grant (P30 CA008748).

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    Sibylle Mitschka & Christine Mayr

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Mitschka, S., Mayr, C. Context-specific regulation and function of mRNA alternative polyadenylation. Nat Rev Mol Cell Biol 23, 779–796 (2022). https://doi.org/10.1038/s41580-022-00507-5

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