title: Interaction profiling identifies the human nuclear exosome targeting complex.
abstract: The RNA exosome is a conserved degradation machinery, which obtains full activity only when associated with cofactors. The most prominent activator of the yeast nuclear exosome is the RNA helicase Mtr4p, acting in the context of the Trf4p/Air2p/Mtr4p polyadenylation (TRAMP) complex. The existence of a similar activator(s) in humans remains elusive. By establishing an interaction network of the human nuclear exosome, we identify the trimeric Nuclear Exosome Targeting (NEXT) complex, containing hMTR4, the Zn-knuckle protein ZCCHC8, and the putative RNA binding protein RBM7. ZCCHC8 and RBM7 are excluded from nucleoli, and consistently NEXT is specifically required for the exosomal degradation of promoter upstream transcripts (PROMPTs). We also detect putative homolog TRAMP subunits hTRF4-2 (Trf4p) and ZCCHC7 (Air2p) in hRRP6 and hMTR4 precipitates. However, at least ZCCHC7 function is restricted to nucleoli. Our results suggest that human nuclear exosome degradation pathways comprise modules of spatially organized cofactors that diverge from the yeast model.
authors.affiliation: Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology, Aarhus University, CF Møllers Allé 3, Building 1130, DK-8000 Aarhus C, Denmark.
authors.forename: Michal
authors.initials: M
authors.lastname: Lubas
authors.forename: Marianne S
authors.initials: MS
authors.lastname: Christensen
authors.forename: Maiken S
authors.initials: MS
authors.lastname: Kristiansen
authors.forename: Michal
authors.initials: M
authors.lastname: Domanski
authors.forename: Lasse G
authors.initials: LG
authors.lastname: Falkenby
authors.forename: Søren
authors.initials: S
authors.lastname: Lykke-Andersen
authors.forename: Jens S
authors.initials: JS
authors.lastname: Andersen
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dziembowski
authors.forename: Torben Heick
authors.initials: TH
authors.lastname: Jensen
mesh_terms: D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D002466:Cell Nucleolus / Q000201:enzymology / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000032:analysis / Q000378:metabolism; D005095:Exoribonucleases / Q000032:analysis / Q000378:metabolism / Q000502:physiology; D063326:Exosome Multienzyme Ribonuclease Complex; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D020365:RNA Helicases / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D012260:Ribonucleases / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; C000596172:RBM7 protein, human; C406243:RBM8A protein, human; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C545342:ZCCHC7 protein, human; C506699:ZCCHC8 protein, human; D004259:DNA-Directed DNA Polymerase; C118146:TENT4A protein, human; D005095:Exoribonucleases; D063326:Exosome Multienzyme Ribonuclease Complex; D012260:Ribonucleases; C077044:EXOSC10 protein, human; C512513:MTREX protein, human; D020365:RNA Helicases