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First published online May 6, 2009
doi: 10.1242/10.1242/jcs.047399

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Origins and activities of the eukaryotic exosome

¹ Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology, C. F. Møllers Allé 1130, University of Aarhus, DK-8000 Aarhus C, Denmark
² Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology, Gustav Wieds Vej 10c, University of Aarhus, DK-8000 Aarhus C, Denmark

View larger version (98K): [in this window] [in a new window]   Fig. 1. Common architecture of RNA degradation complexes. (A) Schematic diagrams illustrate the subunit composition and orientation in bacterial RNase PH (dark green and light green show the inversely oriented arrangement of neighbouring subunits), bacterial PNPase (combined wedges illustrate PH domains from the same polypeptide chain), the archaeal exosome complex and the S. cerevisiae and human exosome complex. The diagrams show the complexes from `underneath', with the RNA-binding cap of the archaeal exosome and S. cerevisiae and human exosome shown as extra wedges behind (blue and purple). In the case of the archaeal exosome, the two-tone wedges indicate that the three RNA-binding proteins in each complex can be either Rrp4, Csl4 or a combination of these. (B) Actual structures of complexes shown in the same orientation, with domains in similar colours to those in (A). The structures shown are PDB 1UDN [RNase PH (Ishii et al., 2003)], 1E3H [PNPase (Symmons et al., 2000)], 2JEA [archaeal exosome (Lorentzen et al., 2007)] and 2NN6 [human exosome (Liu et al., 2006)]. The RNA-binding caps are displayed in the background coloured in grey. Active sites are illustrated by the red colouration of the inorganic phosphate (for RNase PH) or RNA substrate (for the archaeal exosome). (C) Anterior views of PNPase, the archaeal exosome and the S. cerevisiae and human exosomes, with RNA-binding cap proteins shown in blue, purple and cyan. For PNPase, the blue ribbon shows the small part of the S1 domain that is resolved in the current structure (Symmons et al., 2000).

View larger version (60K): [in this window] [in a new window]   Fig. 2. RNA degradation pathways in bacteria and eukaryotes. RNA degradation pathways in some bacteria (such as E. coli) and in eukaryotes require four enzymatic activities: endonucleolysis, oligoadenylation, exonucleolysis and RNA helicase (remodelase) activity. In some bacteria (left), RNA turnover is initiated by the recognition of the 5' monophosphate and subsequent endonucleolytic cleavage by RNase E. The 5' fragment undergoes additional endocleavages, whereas the 3' fragment is oligoadenylated by PAP1 when secondary structure elements are present. The oligo(A) sequence then serves as a tag for recruitment of the bacterial degradosome containing both PNPase and the helicase RhlB (which degrades the RNA completely) or for degradation by RNase II or RNase R. In eukaryotes (right), RNA degradation can also be initiated by endo-cleavage by the exosome component Rrp44 and by 3' oligoadenylation by the nuclear TRAMP complex. The association of the RNA helicase Mtr4 with the exosome allows for the degradation of secondary structure elements. Note that the degradation of fragments upstream of an endocleavage (which might also contain secondary structure elements) can also involve Mtr4 (not shown).

View larger version (30K): [in this window] [in a new window]   Fig. 3. Diverse functions of the eukaryotic exosome. The nuclear and cytoplasmic processes maintained by the eukaryotic exosome are listed on the left and right, respectively. The active nucleases Rrp6 and Rrp44 are indicated above and below the core exosome. Arrows point to the subcellular compartments in which the nucleases have been shown to localise. Also indicated are the organism(s) in which this localisation has been determined. The dashed arrow pointing to the cytoplasm for human Rrp6 indicates that this localisation pattern is still disputed. The compartmentalised processes are further subdivided into pathways of nuclear RNA processing (red arrows) and degradation (orange arrows) on one side, and regulated cytoplasmic RNA turnover (green arrows) and degradation (purple arrows) on the other. Co-factors that are directly linked to the action of the exosome on specific RNA substrates are indicated above and below the arrows (although other pathway-specific factors might be involved in each case). Putative general nuclear and cytoplasmic co-factors are indicated immediately to the left and right of the exosome, respectively. TRAMP and Rrp47 are necessary for the degradation of all listed nuclear species of RNA, whereas it is unclear whether Mpp6 is required for all nuclear exosome functions (Milligan et al., 2008). TUTases have been shown to be necessary for only histone mRNA degradation, and their putative role as universal cytoplasmic co-factors is speculative (Mullen and Marzluff, 2008). Some substrates and co-factors shown are not discussed in the main text: Rnt1 is an endonuclease that cleaves at the base of stem-loop structures that are present in some snRNAs, snoRNAs and pre-mRNAs, and can provide a free 3' end for the exosome. It co-purifies with the Nrd1-Nab3 transcription termination complex, and their activities appear to be coordinated (reviewed by Lykke-Andersen and Jensen, 2007; Schmid and Jensen, 2008). A large group of mRNAs with AU-rich instability elements (AREs) in their 3' UTRs are subject to tight expression control via regulated cytoplasmic turnover. Following stimulation, these ARE-containing mRNAs can be rapidly eliminated by the active recruitment of degradation factors, including the exosome, via ARE-specific adaptor proteins (Chen et al., 2001; Lykke-Andersen and Wagner, 2005; Mukherjee et al., 2002). Similarly, the antiviral protein ZAP can recruit the exosome, and thereby mediate the degradation of certain viral RNAs that contain ZAP-binding elements (ZREs) (Guo et al., 2007). The eRF3/EF1A homologue HBS1 acts together with the endonuclease and eRF1 homologue, Dom34, to mediate the endo-cleavage and subsequent degradation of no-go decay mRNA substrates (Doma and Parker, 2006).

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