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mRNA decay

Cutting in the middle

Nature Reviews Molecular Cell Biology volume 10, page 90 (2009)Cite this article

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The exosome consists of nine catalytically inactive subunits and the Dis3 subunit (also known as Rrp44), which has a catalytic RNB exonuclease domain and a conserved amino-terminal PIN domain. Inspired by recent crystal structures of other PIN domains, which revealed similarities to the catalytic core of the endonuclease RNase H, Lebreton et al. and Schaeffer et al. independently tested whether the PIN domain of Dis3 has nuclease activity. Lebreton et al. found that a RNB-domain mutant that lacks exonucleolytic activity degraded RNA substrates in vitro; however, this ability was lost when additional mutations in the predicted catalytic centre of the PIN domain were present. Schaeffer et al. found that a truncated Dis3 protein had ribonucleolytic activity, which was lost when the PIN domain was mutated. The similarity of degradation profiles of 5′-labelled and 3′-labelled RNA substrates showed that the PIN domain of Dis3 has endonucleolytic activity (exonucleases yield mononucleotides either with 5′- or 3′-labelled substrates, whereas endonucleases yield oligonucleotides with both substrates).

Next, both groups studied the growth phenotypes of wild-type cells, PIN-domain mutants that lacked endonuclease activity and/or mutants that lacked exonuclease activity in vivo. Simultaneous inactivation of the endonucleolytic and exonucleolytic activities of the exosome impaired cell growth. In northern blot analyses of total RNA from wild-type and mutant strains, Lebreton et al. also showed that the endonucleolytic activity of the PIN domain of Dis3 contributes to the degradation of some natural exosome substrates. These data support the physiological role of the PIN domain.

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References

ORIGINAL RESEARCH PAPERS

  1. Lebreton, A. et al. Endonucleolytic RNA cleavage by a eukaryotic exosome. Nature 456, 993–996

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  2. Schaeffer, D. et al. The exosome contains domains with specific endonuclease, exoribonuclease and cytoplasm mRNA decay activities. Nature Struct. Mol. Biol. 7 Dec 2008 (doi:10.1038/nsmb.1528)

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  3. Eberle, A. B. et al. SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells. Nature Struct. Mol. Biol. 7 Dec 2008 (doi:10.1038/nsmb.1530)

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Further Reading

  1. Houseley, J. et al. RNA-quality control by the exosome. Nature Rev. Mol. Cell Biol. 7, 529–539 (2006)

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  2. Garneau, N. L. et al. The highways and byways of mRNA decay. Nature Rev. Mol. Cell Biol. 8, 113–126 (2007)

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Authors
  1. Francesca Cesari
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Cesari, F. Cutting in the middle. Nat Rev Mol Cell Biol 10, 90 (2009). https://doi.org/10.1038/nrm2623

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