Glycogen Synthase Kinase (GSK) 3β Phosphorylates and Protects Nuclear Myosin 1c from Proteasome-Mediated Degradation to Activate rDNA Transcription in Early G1 Cells

Aishe A. Sarshad, Martin Corcoran, Bader Al-Muzzaini, Laura Borgonovo-Brandter, Anne Von Euler, Douglas Lamont, Neus Visa, Piergiorgio Percipalle

    Research output: Contribution to journalArticle

    Abstract

    Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation.

    Original languageEnglish (US)
    Article numbere1004390
    JournalPLoS Genetics
    Volume10
    Issue number6
    DOIs
    StatePublished - Jan 1 2014

    Fingerprint

    Glycogen Synthase Kinase 3
    proteasome endopeptidase complex
    Proteasome Endopeptidase Complex
    Myosins
    myosin
    Ribosomal DNA
    RNA
    transmission electron microscopy
    genomics
    transcription (genetics)
    assay
    degradation
    gene
    cells
    acetylation
    transcriptional activation
    Acetylation
    Transcriptional Activation
    Chromatin
    chromatin

    ASJC Scopus subject areas

    • Ecology, Evolution, Behavior and Systematics
    • Molecular Biology
    • Genetics
    • Genetics(clinical)
    • Cancer Research

    Cite this

    Glycogen Synthase Kinase (GSK) 3β Phosphorylates and Protects Nuclear Myosin 1c from Proteasome-Mediated Degradation to Activate rDNA Transcription in Early G1 Cells. / Sarshad, Aishe A.; Corcoran, Martin; Al-Muzzaini, Bader; Borgonovo-Brandter, Laura; Von Euler, Anne; Lamont, Douglas; Visa, Neus; Percipalle, Piergiorgio.

    In: PLoS Genetics, Vol. 10, No. 6, e1004390, 01.01.2014.

    Research output: Contribution to journalArticle

    Sarshad, AA, Corcoran, M, Al-Muzzaini, B, Borgonovo-Brandter, L, Von Euler, A, Lamont, D, Visa, N & Percipalle, P 2014, 'Glycogen Synthase Kinase (GSK) 3β Phosphorylates and Protects Nuclear Myosin 1c from Proteasome-Mediated Degradation to Activate rDNA Transcription in Early G1 Cells', PLoS Genetics, vol. 10, no. 6, e1004390. https://doi.org/10.1371/journal.pgen.1004390
    Sarshad, Aishe A. ; Corcoran, Martin ; Al-Muzzaini, Bader ; Borgonovo-Brandter, Laura ; Von Euler, Anne ; Lamont, Douglas ; Visa, Neus ; Percipalle, Piergiorgio. / Glycogen Synthase Kinase (GSK) 3β Phosphorylates and Protects Nuclear Myosin 1c from Proteasome-Mediated Degradation to Activate rDNA Transcription in Early G1 Cells. In: PLoS Genetics. 2014 ; Vol. 10, No. 6.
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    abstract = "Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation.",
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