title: Glycogen synthase kinase (GSK) 3β phosphorylates and protects nuclear myosin 1c from proteasome-mediated degradation to activate rDNA transcription in early G1 cells.
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.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Aishe A
authors.initials: AA
authors.lastname: Sarshad
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Corcoran
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Bader
authors.initials: B
authors.lastname: Al-Muzzaini
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Borgonovo-Brandter
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Anne
authors.initials: A
authors.lastname: Von Euler
authors.affiliation: FingerPrints Proteomics Facility, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Douglas
authors.initials: D
authors.lastname: Lamont
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Neus
authors.initials: N
authors.lastname: Visa
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Percipalle
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics; D016193:G1 Phase / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D024461:Myosin Type I / Q000378:metabolism*; D010766:Phosphorylation; D059748:Proteolysis; D034622:RNA Interference; D012318:RNA Polymerase I / Q000235:genetics; D034741:RNA, Small Interfering; D015533:Transcriptional Activation / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D002843:Chromatin; D004275:DNA, Ribosomal; D044783:F-Box Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006657:Histones; D024461:Myosin Type I; D012318:RNA Polymerase I; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C526069:FBXW8 protein, human; C117617:UBR5 protein, human; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C460367:MYO1C protein, human