Messenger RNA

Cleavage (geology)

Alternative splicing

Post-transcriptional modification

Biology

Gene

Precursor mRNA

Cleavage factor

Polyadenylation

Paleontology

Gene isoform

RNA splicing

Cleavage and polyadenylation specificity factor

Computational biology

Coding region

Fracture (geology)

Genetics

Cleavage stimulation factor

Nature Reviews Genetics

Most human genes have multiple sites at which RNA 3ʹ end cleavage and polyadenylation can occur, enabling the expression of distinct transcript isoforms under different conditions. Novel methods to sequence RNA 3′ ends have generated comprehensive catalogues of polyadenylation (poly(A)) sites; their analysis using innovative computational methods has revealed how poly(A) site choice is regulated by core RNA 3ʹ end processing factors, such as cleavage factor I and cleavage and polyadenylation specificity factor, as well as by other RNA-binding proteins, particularly splicing factors. Here, we review the experimental and computational methods that have enabled the global mapping of mRNA and of long non-coding RNA 3ʹ ends, quantification of the resulting isoforms and the discovery of regulators of alternative cleavage and polyadenylation (APA). We highlight the different types of APA-derived isoforms and their functional differences, and illustrate how APA contributes to human diseases, including cancer and haematological, immunological and neurological diseases. In most human genes, RNA 3ʹ end cleavage and polyadenylation can occur at multiple, alternative sites, enabling the expression of distinct transcripts. Novel techniques to sequence RNA 3ʹ ends, coupled with innovative computational methods for studying the list of polyadenylation sites that they generate, have uncovered the roles of alternative cleavage and polyadenylation in both health and disease.

Alternative cleavage and polyadenylation in health and disease