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The regulation and functions of the nuclear RNA exosome complex

Key Points

  • The nuclear RNA exosome complex is involved in 3′ processing of various stable RNA species and is crucial for RNA quality control in the nucleus. It also degrades many types of cryptic transcripts that are generated as a result of pervasive transcription and removes aberrant RNA molecules that failed to mature properly. Disruption of the RNA exosome or its cofactors is associated with human diseases.

  • Targeting substrates to the exosome complex for degradation constitutes a two-step process. Exosome specificity factors recognize and bind to certain features on the target RNA and recruit activating complexes. Unwinding of the RNA substrate by helicases associated with the activating complexes facilitates RNA degradation by the exosome complex.

  • Lack of proper mRNA processing that results in intron retention, transcription read-through or incorrect assembly of ribonucleoprotein particles (mRNPs) in the absence of packaging factors induces transcript degradation by the exosome complex.

  • RNA surveillance by the exosome cooperates with RNA processing to regulate mRNA levels. Both the induction of non-productive RNA processing (such as premature transcription termination or cryptic splicing) or the suppression of proper mRNA processing (resulting in intron retention or read-through transcription) can be coupled with RNA decay by the exosome complex, thus reducing mRNA levels in response to external cues.

  • Several novel functions that have been attributed to the exosome complex include the disassociation of stalled RNA polymerase II and resolving the formation of RNA–DNA hybrids, which are a source of genomic instability. These additional functions seem to be required to enable certain biological processes, such as the DNA damage response and antibody class switch recombination.

Abstract

The RNA exosome complex is the most versatile RNA-degradation machine in eukaryotes. The exosome has a central role in several aspects of RNA biogenesis, including RNA maturation and surveillance. Moreover, it is emerging as an important player in regulating the expression levels of specific mRNAs in response to environmental cues and during cell differentiation and development. Although the mechanisms by which RNA is targeted to (or escapes from) the exosome are still not fully understood, general principles have begun to emerge, which we discuss in this Review. In addition, we introduce and discuss novel, previously unappreciated functions of the nuclear exosome, including in transcription regulation and in the maintenance of genome stability.

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Figure 1: Structure of exosome complex isoforms.
Figure 2: Conserved features of RNA targeting to the exosome.
Figure 3: RNA surveillance by the exosome cooperates with RNA processing to regulate mRNA levels.
Figure 4: Potential mechanisms of R-loop resolution by the exosome complex.

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Acknowledgements

The authors apologize to the many colleagues whose work could not be cited owing to limited space. This work was supported by a research fellowship from the German Research Foundation (DFG) (KI1657/1-1) to C.K., a studentship by the UK Medical Research Council (MRC) to S.W. and Research and Career and Senior Research fellowships from the Wellcome Trust to L.V. (WT088359MA and WT106994MA).

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Glossary

Spinal muscular atrophy

A neuromuscular disorder characterized by degeneration of specific cells within the spinal cord that leads to muscle weakness and atrophy.

Pontocerebellar hypoplasias

A group of severe neurodegenerative disorders that affect growth and function of the brain, resulting in delayed development and, frequently, early death.

PH-like proteins

Proteins that resemble the bacterial ribonuclease PH, which is a phosphorolytic exoribonuclease.

DExH-box

A short motif that characterizes a family of RNA- or DNA-binding, ATP-hydrolysing proteins, many of which are helicases. The DEAD-box is a similar motif.

Non-canonical poly(A) polymerase

Member of a conserved subclass of nucleotidyl transferases. Related to the canonical poly(A) polymerase, which catalyses the addition of poly(A) tails to mRNAs, but with diverse substrates and functions.

Zn-knuckle

A zinc-binding structural motif that frequently mediates interactions with nucleic acids.

YTH domain

A conserved RNA-binding domain named after the splicing factor YT521-B. YTH domains of some proteins specifically recognize methylated adenosines.

Sm ring

Heptameric protein complex that associates with Sm sites located at the 3′ end of small nuclear RNAs (snRNAs) and telomerase RNA and stabilizes them.

sno-lncRNAs

A class of long non-coding RNAs (lncRNAs) that is protected from degradation by the presence of a small nucleolar RNA (snoRNA) fold. Their biological function is unknown.

SR proteins

A conserved family of proteins involved in RNA splicing, characterized by a domain with Ser and Arg repeats.

Cryptic introns

Introns that are usually spliced at low frequency. Their splicing can be activated in response to external cues and does not necessarily generate a functional transcript.

Ataxia with oculomotor apraxia 2

(AOA2). A neurodegenerative disorder characterized by juvenile onset of progressive cerebellar ataxia and peripheral neuropathy.

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Kilchert, C., Wittmann, S. & Vasiljeva, L. The regulation and functions of the nuclear RNA exosome complex. Nat Rev Mol Cell Biol 17, 227–239 (2016). https://doi.org/10.1038/nrm.2015.15

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