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Nopp140-chaperoned 2'-O-methylation of small nuclear RNAs in Cajal bodies ensures splicing fidelity.
Bizarro, Jonathan; Deryusheva, Svetlana; Wacheul, Ludivine; Gupta, Varun; Ernst, Felix G M; Lafontaine, Denis L J; Gall, Joseph G; Meier, U Thomas.
  • Bizarro J; Albert Einstein College of Medicine, Bronx, New York 10461, USA.
  • Deryusheva S; Carnegie Institution for Science, Baltimore, Maryland 21218, USA.
  • Wacheul L; RNA Molecular Biology, Fonds National de la Recherche Scientifique (FRS/FNRS), Université Libre de Bruxelles (ULB), B-6041 Gosselies, Belgium.
  • Gupta V; Albert Einstein College of Medicine, Bronx, New York 10461, USA.
  • Ernst FGM; RNA Molecular Biology, Fonds National de la Recherche Scientifique (FRS/FNRS), Université Libre de Bruxelles (ULB), B-6041 Gosselies, Belgium.
  • Lafontaine DLJ; RNA Molecular Biology, Fonds National de la Recherche Scientifique (FRS/FNRS), Université Libre de Bruxelles (ULB), B-6041 Gosselies, Belgium.
  • Gall JG; Carnegie Institution for Science, Baltimore, Maryland 21218, USA.
  • Meier UT; Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Genes Dev ; 35(15-16): 1123-1141, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1322683
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ABSTRACT
Spliceosomal small nuclear RNAs (snRNAs) are modified by small Cajal body (CB)-specific ribonucleoproteins (scaRNPs) to ensure snRNP biogenesis and pre-mRNA splicing. However, the function and subcellular site of snRNA modification are largely unknown. We show that CB localization of the protein Nopp140 is essential for concentration of scaRNPs in that nuclear condensate; and that phosphorylation by casein kinase 2 (CK2) at ∼80 serines targets Nopp140 to CBs. Transiting through CBs, snRNAs are apparently modified by scaRNPs. Indeed, Nopp140 knockdown-mediated release of scaRNPs from CBs severely compromises 2'-O-methylation of spliceosomal snRNAs, identifying CBs as the site of scaRNP catalysis. Additionally, alternative splicing patterns change indicating that these modifications in U1, U2, U5, and U12 snRNAs safeguard splicing fidelity. Given the importance of CK2 in this pathway, compromised splicing could underlie the mode of action of small molecule CK2 inhibitors currently considered for therapy in cholangiocarcinoma, hematological malignancies, and COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Phosphoproteins / Nuclear Proteins / RNA, Small Nuclear / RNA Splicing / Interstitial Cells of Cajal / Methylation Limits: Humans Language: English Journal: Genes Dev Journal subject: Molecular Biology Year: 2021 Document Type: Article Affiliation country: Gad.348660.121

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Phosphoproteins / Nuclear Proteins / RNA, Small Nuclear / RNA Splicing / Interstitial Cells of Cajal / Methylation Limits: Humans Language: English Journal: Genes Dev Journal subject: Molecular Biology Year: 2021 Document Type: Article Affiliation country: Gad.348660.121