Abstract
The majority of mammalian genes contain one or more alternative polyadenylation sites. Choice of polyadenylation sites was suggested as one of the underlying mechanisms for generating longer/shorter transcript isoforms. Here, we demonstrate that mature mRNA transcripts can undergo additional cleavage and polyadenylation at a proximal internal site in the 3′-UTR, resulting in two stable, autonomous, RNA fragments: a coding sequence with a shorter 3′-UTR (body) and an uncapped 3′-UTR sequence downstream of the cleavage point (tail). Analyses of the human transcriptome has revealed thousands of such cleavage positions, suggesting a widespread post-transcriptional phenomenon producing thousands of stable 3′-UTR RNA tails that exist alongside their transcripts of origin. By analyzing the impact of microRNAs, we observed a significantly stronger effect for microRNA regulation at the body compared to the tail fragments. Our findings open a variety of future research prospects and call for a new perspective on 3′-UTR-dependent gene regulation.
Highlights
The majority of mammalian genes contain one or more alternative polyadenylation sites
By re-annotating the human transcriptome for novel cleavage positions, we show stronger regulatory effects by miRNA sites in the body fragment compared to 3′-UTR sites downstream of the cleavage point
Using a variety of molecular and genomic methods, we show that thousands of mature poly(A) mRNAs, located mainly in the cytoplasm, are cleaved and polyadenylated posttranscriptionally at APA sites in their 3′-UTRs, and regions that were considered to be a part of the canonical transcripts are autonomous uncapped “tail” units
Summary
The majority of mammalian genes contain one or more alternative polyadenylation sites. We demonstrate that mature mRNA transcripts can undergo additional cleavage and polyadenylation at a proximal internal site in the 3′-UTR, resulting in two stable, autonomous, RNA fragments: a coding sequence with a shorter 3′-UTR (body) and an uncapped 3′-UTR sequence downstream of the cleavage point (tail). The majority of mammalian genes undergo alternative polyadenylation (APA) in the nucleus to generate RNA isoforms with shorter 3′-UTRs. Accumulation of transcripts with short 3′-UTRs is widespread across tissues and is positively correlated with cell proliferation[1], membrane protein localization[2], and several diseases including cancer[3,4,5,6]. By re-annotating the human transcriptome for novel cleavage positions, we show stronger regulatory effects by miRNA sites in the body fragment compared to 3′-UTR sites downstream of the cleavage point
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