Controlling nuclear RNA levels

Abstract

RNA turnover is an integral part of cellular RNA homeostasis and gene expression regulation. Whereas the cytoplasmic control of protein-coding mRNA is often the focus of study, we discuss here the less appreciated role of nuclear RNA decay systems in controlling RNA polymerase II (RNAPII)-derived transcripts. Historically, nuclear RNA degradation was found to be essential for the functionalization of transcripts through their proper maturation. Later, it was discovered to also be an important caretaker of nuclear hygiene by removing aberrant and unwanted transcripts. Recent years have now seen a set of new protein complexes handling a variety of new substrates, revealing functions beyond RNA processing and the decay of non-functional transcripts. This includes an active contribution of nuclear RNA metabolism to the overall cellular control of RNA levels, with mechanistic implications during cellular transitions.

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Fig. 1: Nuclear RNA decay opportunities around protein-coding genes.
Fig. 2: Escaping nuclear decay.
Fig. 3: RNA homeostasis model.

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Acknowledgements

Work in the T.H.J. laboratory is supported by the Danish National Research Council, the Lundbeck and Novo Nordisk Foundations and the European Research Council (grant 339953).

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Nature Reviews Genetics thanks Stefan Bresson, Alain Jacquier and David Tollervey for their contribution to the peer review of this work.

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Glossary

RNA exosome

A multisubunit protein complex harbouring 3ʹ−5ʹ exoribonucleolytic and endoribonucleolytic activities. The exosome is conserved in archaea and eukaryotic lineages (see also Boxes 1,2).

Transcription termination

The process whereby a transcribing RNA polymerase (RNAP) dissociates from its genome template.

Small nuclear RNAs

(snRNAs). Also termed U snRNAs due to their high uridine content, snRNAs are packaged with proteins into small nuclear ribonucleoprotein (snRNP) complexes and form part of the spliceosome complex (for example, U1, U2, U4, U5, U6, U11, U12, U4atac and U6atac snRNPs) or histone pre-mRNA processing complex (for example, U7 snRNP).

Small nucleolar RNAs

(snoRNAs). RNAs containing conserved H/ACA or C/D box motifs that are packaged with proteins into small nucleolar ribonucleoprotein (snoRNP) complexes that guide the pseudouridylation or methylation of ribosomal RNAs (rRNAs) and other RNAs. Despite their name, snoRNAs are not necessarily restricted to the nucleolus.

Cryptic unstable transcripts

(CUTs). Highly unstable short Saccharomyces cerevisiae RNAs that are often encoded upstream and antisense of protein-coding genes.

Small nuclear ribonucleoprotein

(snRNP). A particle consisting of a small nuclear RNA (snRNA) and its protein-binding partners.

Nuclear exosome targeting

(NEXT). This complex is a mammalian nuclear RNA exosome adaptor containing the MTR4, RBM7 and ZCCHC8 proteins. It is involved in targeting the exosome to short and non-sequence-specific RNAs.

Torpedo model

A model that suggests that transcription termination is caused by the nuclear 5ʹ−3ʹ exonuclease (Rat1 in Saccharomyces cerevisae; XRN2 in mammals) degrading the nascent RNA attached to RNA polymerase (RNAP) after an endonucleolytic cleavage event, akin to a torpedo chasing after a target.

Co-transcriptional cleavage sites

(CoTCs). Regions positioned downstream of annotated poly(A) sites that are subjected to endonucleolytic cleavage to facilitate transcription termination. CoTCs are poorly defined and the mechanisms underlying RNA cleavage remain to be uncovered.

Roadblock terminators

Genomic regions that cause ‘roadblock’ transcription termination, for example, when they are occupied by a tightly bound DNA-binding protein that prevents RNA polymerase (RNAP) from transcribing beyond this site.

Poly(A) RNA exosome targeting

(PAXT). Connection made up of a mammalian nuclear RNA exosome adaptor that contains the MTR4, ZFC3H1 and PABPN1 proteins and is involved in recruiting the exosome to polyadenylated RNAs.

Long non-coding RNAs

(lncRNAs). RNAs that are most often defined as non-protein-coding transcripts longer than 200 nucleotides.

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Schmid, M., Jensen, T.H. Controlling nuclear RNA levels. Nat Rev Genet 19, 518–529 (2018). https://doi.org/10.1038/s41576-018-0013-2

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