title: Identification of a Nuclear Exosome Decay Pathway for Processed Transcripts.
abstract: The RNA exosome is fundamental for the degradation of RNA in eukaryotic nuclei. Substrate targeting is facilitated by its co-factor Mtr4p/hMTR4, which links to RNA-binding protein adaptors. One example is the trimeric human nuclear exosome targeting (NEXT) complex, which is composed of hMTR4, the Zn-finger protein ZCCHC8, and the RNA-binding factor RBM7. NEXT primarily targets early and unprocessed transcripts, which demands a rationale for how the nuclear exosome recognizes processed RNAs. Here, we describe the poly(A) tail exosome targeting (PAXT) connection, which comprises the ZFC3H1 Zn-knuckle protein as a central link between hMTR4 and the nuclear poly(A)-binding protein PABPN1. Individual depletion of ZFC3H1 and PABPN1 results in the accumulation of common transcripts that are generally both longer and more extensively polyadenylated than NEXT substrates. Importantly, ZFC3H1/PABPN1 and ZCCHC8/RBM7 contact hMTR4 in a mutually exclusive manner, revealing that the exosome targets nuclear transcripts of different maturation status by substituting its hMTR4-associating adaptors.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, Building 1130, DK-8000 Aarhus C, Denmark.
authors.forename: Nicola
authors.initials: N
authors.lastname: Meola
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, Building 1130, DK-8000 Aarhus C, Denmark.
authors.forename: Michal
authors.initials: M
authors.lastname: Domanski
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, Building 1130, DK-8000 Aarhus C, Denmark; The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloesvej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Evdoxia
authors.initials: E
authors.lastname: Karadoulama
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloesvej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, Building 1130, DK-8000 Aarhus C, Denmark.
authors.forename: Coline
authors.initials: C
authors.lastname: Gentil
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense, Denmark.
authors.forename: Dennis
authors.initials: D
authors.lastname: Pultz
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloesvej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Vitting-Seerup
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, Building 1130, DK-8000 Aarhus C, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Lykke-Andersen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense, Denmark.
authors.forename: Jens S
authors.initials: JS
authors.lastname: Andersen
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloesvej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Albin
authors.initials: A
authors.lastname: Sandelin
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, Building 1130, DK-8000 Aarhus C, Denmark. Electronic address: thj@mbg.au.dk.
authors.forename: Torben Heick
authors.initials: TH
authors.lastname: Jensen
mesh_terms: D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011061:Poly A / Q000235:genetics / Q000378:metabolism; D039122:Poly(A)-Binding Protein I / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D020365:RNA Helicases / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; C000596172:RBM7 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C506699:ZCCHC8 protein, human; C000598591:ZFC3H1 protein, human; D011061:Poly A; D063326:Exosome Multienzyme Ribonuclease Complex; C512513:MTREX protein, human; D020365:RNA Helicases
keywords: NEXT complex; PAXT connection; RNA exosome; nuclear RNA decay; poly(A) tail