Nuclear RNA surveillance: role of TRAMP in controlling exosome specificity

Abstract

The advent of high throughput sequencing technologies has revealed that pervasive transcription generates RNAs from nearly all regions of eukaryotic genomes. Normally these transcripts undergo rapid degradation by a nuclear RNA surveillance system primarily featuring the RNA exosome. This multimeric protein complex plays a critical role in the efficient turnover and processing of a vast array of RNAs in the nucleus. Despite its initial discovery over a decade ago, important questions remain concerning the mechanisms that recruit and activate the nuclear exosome. Specificity and modulation of exosome activity requires additional protein cofactors, including the conserved TRAMP polyadenylation complex. Recent studies suggest that helicase and RNA binding subunits of TRAMP direct RNA substrates for polyadenylation, which enhances their degradation by Dis3/Rrp44 and Rrp6, the two exosome associated ribonucleases. These findings indicate that the exosome and TRAMP have evolved highly flexible functions that allow recognition of a wide range of RNA substrates. This flexibility provides the nuclear RNA surveillance system with the ability to regulate the levels of a broad range of coding and non-coding RNAs, which results in profound effects on gene expression, cellular development, gene silencing and heterochromatin formation. This review summarizes recent findings on the nuclear RNA surveillance complexes, and speculates upon possible mechanisms for TRAMP-mediated substrate recognition and exosome activation.

Global characterization of the Dicer-like protein DrnB roles in miRNA biogenesis in the social amoeba Dictyostelium discoideum

“…The TRAMP complex is involved in adding short A-tails to e.g. misfolded or improperly processed ncRNAs such as snRNA and tRNAs and thereby target them for degradation by the exosome [65,66]. In Arabidopsis, TRAMP-like and exosome activities have been suggested to be responsible for oligoadenylation and subsequent degradation of intermediates of miRNA biogenesis.…”

Short intronic repeat sequences facilitate circular RNA production

“…We propose that the kinetics of splicing are likely slowed during the circularization process, possibly because pairing of the intronic repeats interferes with exon definition, thereby preventing the cotranscriptional formation of a fully spliced linear mRNA. By forming a stable 39 end, the transcript is able to avoid degradation by nuclear RNA surveillance mechanisms (for review, see Schmidt and Butler 2013) and allow the spliceosome and other regulatory factors to determine whether to produce a linear mRNA or a circular RNA. Alternatively, as polyadenylation and splicing can be functionally coupled (Niwa and Berget 1991), the 39 end processing machinery may recruit or otherwise directly interact with circular RNA biogenesis factors, thereby promoting circularization.…”

Widespread exon skipping triggers degradation by nuclear RNA surveillance in fission yeast

“…The exosome is a multiprotein complex containing nine noncatalytic core subunits, which interact in the nucleus with the two catalytic subunits, Rrp6 and Dis3, that confer 3 ′ -5 ′ exoribonuclease and endoribonuclease activities, respectively (Houseley et al 2006;Garneau et al 2007;Schmid and Jensen 2008;Schneider and Tollervey 2013). RNA degradation by the exosome is facilitated by polyadenylation activity of the TRAMP complex (LaCava et al 2005;Schmidt and Butler 2013), by helicase activity (Houseley et al 2006;Schmidt and Butler 2013), and by decapping and deadenylation (Garneau et al 2007;Arribas-Layton et al 2013). In budding yeast, unspliced and partially spliced transcripts, as well as transcripts with abnormal exon skipping, are actively degraded by the nuclear exosome, the 5 ′ -3 ′ nuclear exonuclease Rat1 (Dhp1 in fission yeast), or the RNase III endonuclease Rnt1 (Egecioglu et al 2012;Sayani and Chanfreau 2012).…”