RNA-quality control by the exosome

Abstract

The exosome complex of 3′→5′ exonucleases is an important component of the RNA-processing machinery in eukaryotes. This complex functions in the accurate processing of nuclear RNA precursors and in the degradation of RNAs in both the nucleus and the cytoplasm. However, it has been unclear how different classes of substrate are distinguished from one another. Recent studies now provide insights into the regulation and structure of the exosome, and they reveal striking similarities between the process of RNA degradation in bacteria and eukaryotes.

Key Points

  • The processing and degradation of RNA sequences is ubiquitous, and these activities can be separated into different classes on the basis of their mechanism and function. The clearest functional differences exist between RNA maturation that will generate a usable RNA from its precursor and RNA degradation that will destroy the RNA completely.

  • There is mounting evidence that all RNA-maturation pathways in eukaryotes are continuously monitored by surveillance systems. A key component of the RNA-surveillance machinery is the exosome complex of 3′→5′ exonucleases. On different substrates this complex is responsible for either total RNA degradation or accurate RNA processing, implying a precise distinction between different classes of substrate.

  • Despite the presence of multiple catalytic sites, the purified yeast exosome is almost entirely inactive. However, several activating cofactors have recently been identified.

  • The role of polyadenylation in eukaryotic cells seems different on either side of the nuclear envelope. The long poly(A) tails on cytoplasmic mRNAs promote stability and translation. By contrast, defective nuclear RNAs are identified and 'tagged' with short oligo(A) tails by the TRAMP polyadenylation complex prior to degradation by the exosome. Such tagging of RNAs by polyadenylation could be conceptually similar to the role of polyubiquitylation in targeting proteins for degradation by the proteasome complex.

  • Key features of RNA degradation have been conserved throughout evolution. Recent structural analyses indicate that the eukaryotic exosome resembles a complex between bacterial PNPase and RNase II, the most active degradative exonucleases in Escherichia coli lysates. Moreover, the role of eukaryotic poly(A) polymerases in targeting nuclear RNAs for degradation is strikingly similar to the role of oligoadenylation in stimulating RNA degradation in bacteria.

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Figure 1: Structure of the exosome complex.
Figure 2: Activation of the exosome.
Figure 3: Roles of polyadenylation in eukaryotic cells.

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Glossary

Small nucleolar RNA

(snoRNA). A small RNA molecule that functions in ribosome biogenesis in the nucleolus. Most snoRNAs direct site-specific base modification in the pre-ribosomal RNAs, whereas a small number are required for pre-ribosomal RNA cleavage.

Small nuclear RNAs

Five small RNA species (U1, U2, U4, U5 and U6) that form the core of the pre-mRNA-splicing system in the nucleus.

Ribonucleoprotein particle

A complex of proteins and RNA. In many cases, the proteins can recognize their cognate mRNA molecules (selective binding) and mediate their delivery to specific regions within the cell.

Nonsense-mediated decay

The process by which the cell destroys mRNAs in which translation has been prematurely terminated owing to the presence of a nonsense codon within the coding region.

Non-stop decay

An RNA-degradation pathway for mRNAs that do not contain a translation-termination codon and in which the translating ribosomes stall at the end of the transcript.

No-go decay

An RNA-degradation pathway that is induced by the stalling of a translating ribosome. The RNA is cleaved in the vicinity of the stalled ribosome, and this is followed by exonuclease degradation of the cleaved fragments. The 5′ fragment is degraded by the exosome, whereas the 3′ fragment is degraded by the 5′ exonuclease Xrn1.

S1 domain

A putative RNA-binding domain that was initially identified in ribosomal protein S1, and that is present in a large number of RNA-associated proteins.

KH domain

An evolutionarily conserved single-stranded-RNA-binding domain that was originally identified in the human heterogeneous nuclear (hn)RNP K protein.

Proteasome

A large multisubunit protease complex that selectively degrades multi-ubiquitylated proteins. It contains a 20S particle that has catalytic activity and two regulatory 19S particles.

DExH-box RNA helicases

RNA helicases that are related to DEAD-box proteins, and that contain an Asp-Glu-x-His (DExH) conserved motif.

ARE-mediated mRNA degradation

A process of rapid degradation of mRNAs that is mediated by the recruitment of the exosome by factors that bind to A+U-rich sequence elements (AREs) that are generally located in the 3′ untranslated region of the mRNAs.

Zinc-knuckle domain

This CX2CX4HX4C motif binds two zinc atoms and has been implicated in interactions between proteins and with single-stranded nucleic acids.

5′ cap structure

A structure that is located at the 5′ end of eukaryotic mRNAs and that consists of m7GpppN (where m7G represents 7-methylguanosine, p represents a phosphate group and N represents any base).

P-body

(Processing body). The cytoplasmic site of mRNA degradation. mRNAs on which translation has ceased are released from the polysome pool and recruited to P-bodies, where they accumulate together with the mRNA decapping and 5′-degradation machinery.

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