Trends in Biochemical Sciences
ReviewAlternative cleavage and polyadenylation: the long and short of it
Section snippets
APA is widespread in eukaryotes
The mechanism of 3′ end processing of nascent transcripts in eukaryotic cells is determined by the type of RNA polymerase used for transcription and specific signals embedded in the transcript (reviewed in [1]). Except for most replication-dependent histone mRNAs in metazoans, and some protozoans (reviewed in [2]), all pre-mRNAs are processed by C/P, which involves endonucleolytic cleavage of the nascent RNA and synthesis of a poly(A) tail (reviewed in [3]), and is a necessary prelude to
APA impacts the cellular transcriptome and proteome
A given gene can encode transcripts with multiple pAs located in different regions (Figure 1). With respect to the impact on protein-coding, alternative pAs in the 3′-most exon typically leads to variable 3′ UTRs, whereas pAs in upstream introns and exons cause both coding sequence (CDS) and 3′ UTR changes. Alternative pAs in introns can be further divided into two subtypes depending on the configuration of the terminal exon in which they reside: namely, skipped terminal exons (a whole exon is
Tissue specificity
Studies of individual genes over the past two decades have reported hundreds of cases in which APA isoforms are differentially expressed under different cellular conditions (some early studies are reviewed in [35]). Global analysis of APA isoforms using expressed sequence tag (EST) libraries has indicated variation of expression in different tissues 25, 36, suggesting that APA isoform expression is not stochastic. Some human tissues have been found to have a global tendency favoring certain
Regulation of core C/P factor expression
The core components of the mammalian C/P machinery include ~15 polypeptides, most of which exist in multisubunit subcomplexes (Box 3 and Figure 3). Regulation of APA by modulation of core factor expression was first demonstrated for cleavage stimulation factor (CstF)-64, one of the subunits of the CstF complex (Box 3), which is strongly upregulated during B cell maturation, resulting in higher usage of the upstream intronic pA in the IgM pre-mRNA [28] (discussed previously). This has been shown
Concluding remarks
Building upon biochemical studies of 3′ end processing in the past three decades, recent advances at the molecular and systems levels concerning APA have stimulated interest in comprehending this dynamic process and its widespread implications for regulation of gene expression and cell growth control. Many questions remain to be addressed in the coming years. For instance, with the availability of powerful deep sequencing methods to study APA isoforms, thorough understanding of APA in different
Acknowledgments
We thank our laboratory members for helpful discussions. We apologize for not citing many important papers related to the topic owing to space limitation. This work was funded by grants GM 84089 (B.T.) and GM 28983 (J.L.M.) from National Institutes of Health.
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