Co-transcriptional degradation of aberrant pre-mRNA by Xrn2

Abstract

Eukaryotic protein‐coding genes are transcribed as pre‐mRNAs that are matured by capping, splicing and cleavage and polyadenylation. Although human pre‐mRNAs can be long and complex, containing multiple introns and many alternative processing sites, they are usually processed co‐transcriptionally. Mistakes during nuclear mRNA maturation could lead to potentially harmful transcripts that are important to eliminate. However, the processes of human pre‐mRNA degradation are not well characterised in the human nucleus. We have studied how aberrantly processed pre‐mRNAs are degraded and find a role for the 5′→3′ exonuclease, Xrn2. Xrn2 associates with and co‐transcriptionally degrades nascent β‐globin transcripts, mutated to inhibit splicing or 3′ end processing. Importantly, we provide evidence that many endogenous pre‐mRNAs are also co‐transcriptionally degraded by Xrn2 when their processing is inhibited by Spliceostatin A. Our data therefore establish a previously unknown function for Xrn2 and an important further aspect of pre‐mRNA metabolism that occurs co‐transcriptionally.