A role for the exosome in the in vivo degradation of unstable mRNAs

In mammals, the mRNAs encoding many proteins involved in inflammation bear destabilizing AU-rich elements (AREs) in the 3'-untranslated region. The exosome, a complex of 3' --> 5' exonucleases, is rate limiting in the destruction of such mRNAs in a mammalian in vitro system, but a...

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Bibliographic Details
Published in:RNA (Cambridge) 2003-12, Vol.9 (12), p.1491-1501
Main Authors: Haile, Simon, Estevez, Antonio M, Clayton, Christine
Format: Article
Language:English
Subjects:
3' ^AUntranslated region
3' Untranslated Regions
Animals
Base Sequence
Blotting, Northern
DNA Primers
Exosomes
Hydrolysis
Kinetics
Organelles - physiology
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - metabolism
RNA, Protozoan - metabolism
Trypanosoma brucei
Trypanosoma brucei brucei - genetics
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Summary:In mammals, the mRNAs encoding many proteins involved in inflammation bear destabilizing AU-rich elements (AREs) in the 3'-untranslated region. The exosome, a complex of 3' --> 5' exonucleases, is rate limiting in the destruction of such mRNAs in a mammalian in vitro system, but a role in vivo has not been demonstrated. The phenomenon of ARE-mediated degradation also occurs in the protist parasite Trypanosoma brucei. Messenger RNAs with 3'-untranslated region U-rich elements, which strongly resemble AREs, are extremely unstable in the trypanosome form that parasitizes mammals. The first step in degradation of these mRNAs in vivo is rapid destruction of the 3'-untranslated region; subsequently the mRNA is destroyed by exonucleases acting in both 5' --> 3' and 3' --> 5' directions. We here investigated the roles of three subunits of the trypanosome exosome complex, RRP45, RRP4, and CSL4, in this process, depleting the individual subunits in vivo by inducible RNA interference. RRP45 depletion, which probably disrupts exosome integrity, caused a delay in the onset of degradation of the very unstable RNAs, but did not affect degradation of more stable species. Depletion of RRP4 or CSL4 does not affect the stability of the residual exosome and did not change mRNA degradation kinetics. We conclude that the exosome is required for the initiation of rapid degradation of unstable mRNAs in trypanosomes.
ISSN:1355-8382
1469-9001
DOI:10.1261/rna.5940703