title: The Polyadenosine RNA-binding Protein, Zinc Finger Cys3His Protein 14 (ZC3H14), Regulates the Pre-mRNA Processing of a Key ATP Synthase Subunit mRNA.
abstract: Polyadenosine RNA-binding proteins (Pabs) regulate multiple steps in gene expression. This protein family includes the well studied Pabs, PABPN1 and PABPC1, as well as the newly characterized Pab, zinc finger CCCH-type containing protein 14 (ZC3H14). Mutations in ZC3H14 are linked to a form of intellectual disability. To probe the function of ZC3H14, we performed a transcriptome-wide analysis of cells depleted of either ZC3H14 or the control Pab, PABPN1. Depletion of PABPN1 affected ∼17% of expressed transcripts, whereas ZC3H14 affected only ∼1% of expressed transcripts. To assess the function of ZC3H14 in modulating target mRNAs, we selected the gene encoding the ATP synthase F0subunit C (ATP5G1) transcript. Knockdown of ZC3H14 significantly reduced ATP5G1 steady-state mRNA levels. Consistent with results suggesting that ATP5G1 turnover increases upon depletion of ZC3H14, double knockdown of ZC3H14 and the nonsense-mediated decay factor, UPF1, rescues ATP5G1 transcript levels. Furthermore, fractionation reveals an increase in the amount of ATP5G1 pre-mRNA that reaches the cytoplasm when ZC3H14 is depleted and that ZC3H14 binds to ATP5G1 pre-mRNA in the nucleus. These data support a role for ZC3H14 in ensuring proper nuclear processing and retention of ATP5G1 pre-mRNA. Consistent with the observation that ATP5G1 is a rate-limiting component for ATP synthase activity, knockdown of ZC3H14 decreases cellular ATP levels and causes mitochondrial fragmentation. These data suggest that ZC3H14 modulates pre-mRNA processing of select mRNA transcripts and plays a critical role in regulating cellular energy levels, observations that have broad implications for proper neuronal function.
authors: From the Department of Biochemistry and.|the Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia 30322.
authors: Callie P
authors: CP
authors: Wigington
authors: From the Department of Biochemistry and.|the Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia 30322.
authors: Kevin J
authors: KJ
authors: Morris
authors: From the Department of Biochemistry and.|the Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia 30322.
authors: Laura E
authors: LE
authors: Newman
authors: From the Department of Biochemistry and acorbe2@emory.edu.|the Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia 30322.
authors: Anita H
authors: AH
authors: Corbett
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D039122:Poly(A)-Binding Protein I / Q000235:genetics / Q000378:metabolism*; D039102:Poly(A)-Binding Proteins; D020365:RNA Helicases; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; D039102:Poly(A)-Binding Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D015534:Trans-Activators; C522547:ZC3H14 protein, human; D025261:Mitochondrial Proton-Translocating ATPases; D020365:RNA Helicases; C101828:UPF1 protein, human
keywords: ATP synthase; MSUT2; Nab2; RNA; RNA processing; RNA splicing; RNA-binding protein; ZC3H14; post-transcriptional regulation