Abstract
Polymerases and exonucleases act on 3' ends of nascent RNAs to promote their maturation or degradation but how the balance between these activities is controlled to dictate the fates of cellular RNAs remains poorly understood. Here, we identify a central role for the human DEDD deadenylase TOE1 in distinguishing the fates of small nuclear (sn)RNAs of the spliceosome from unstable genome-encoded snRNA variants. We found that TOE1 promotes maturation of all regular RNA polymerase II transcribed snRNAs of the major and minor spliceosomes by removing posttranscriptional oligo(A) tails, trimming 3' ends, and preventing nuclear exosome targeting. In contrast, TOE1 promotes little to no maturation of tested U1 variant snRNAs, which are instead targeted by the nuclear exosome. These observations suggest that TOE1 is positioned at the center of a 3' end quality control pathway that selectively promotes maturation and stability of regular snRNAs while leaving snRNA variants unprocessed and exposed to degradation in what could be a widespread mechanism of RNA quality control given the large number of noncoding RNAs processed by DEDD deadenylases.
Highlights
A large number of polymerases and exonucleases act on RNA 3′ ends to control the destiny of newly transcribed RNAs, promoting their maturation or degradation
The importance of the DEDD family deadenylases is underscored by genetic mutations in poly(A)-specific ribonuclease (PARN) and TOE1 genes leading to specific subtypes of human disorders dyskeratosis congenita and pontocerebellar hypoplasia (PCH), respectively (Dhanraj et al 2015; Stuart et al 2015; Tummala et al 2015; Lardelli et al 2017)
We present evidence that the human DEDD-deadenylase TOE1 promotes the maturation of RNA polymerase II transcribed snRNAs in competition with degradation by the nuclear exosome in a process that helps differentiate the fates of regular spliceosomal snRNAs from genome-encoded unstable U1 snRNA variants (Fig. 7)
Summary
A large number of polymerases and exonucleases act on RNA 3′ ends to control the destiny of newly transcribed RNAs, promoting their maturation or degradation. One class of small RNAs processed by a DEDD family deadenylase is RNA polymerase II transcribed snRNAs, which undergo a complex maturation pathway before forming the catalytic core of the spliceosome. These RNAs are cotranscriptionally m7G-capped at the 5′ end by capping and methylation enzymes (Salditt-Georgieff et al 1980) and cleaved at the 3′ end by the Integrator complex (Baillat et al 2005), which leaves a short genome-encoded 3′ tail. We recently identified the DEDD family deadenylase TOE1 as an enzyme critical for snRNA 3′ end trimming in human cells (Lardelli et al 2017). Depletion of TOE1 had been previously observed to result in a pre-mRNA splicing defect (Fong et al 2013) but how TOE1-mediated snRNA 3′ end processing is integrated with snRNP biogenesis has remained unknown
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