title: The Chromatin-Associated Phf12 Protein Maintains Nucleolar Integrity and Prevents Premature Cellular Senescence.
abstract: Pf1, also known as Phf12 (plant homeodomain [PHD] zinc finger protein 12), is a member of the PHD zinc finger family of proteins. Pf1 associates with a chromatin-interacting protein complex comprised of MRG15, Sin3B, and histone deacetylase 1 (HDAC1) that functions as a transcriptional modulator. The biological function of Pf1 remains largely elusive. We undertook the generation ofPf1knockout mice to elucidate its physiological role. We demonstrate thatPf1is required for mid- to late gestation viability.Pf1inactivation impairs the proliferative potential of mouse embryonic fibroblasts (MEFs) and is associated with a significant decrease in bromodeoxyuridine incorporation; an increase in senescence-associated β-galactosidase (SA-β-Gal) activity, a marker of cellular senescence; and elevated levels of phosphorylated H2AX (γ-H2A.X), a marker associated with DNA double-strand breaks. Analysis of transcripts differentially expressed in wild-type and Pf1-deficient cells revealed the impact of Pf1 in multiple regulatory arms of the ribosome biogenesis pathways. Strikingly, assessment of the morphology of the nucleoli exposed an abnormal nucleolar structure in Pf1-deficient cells. Finally, proteomic analysis of the Pf1-interacting complexes highlighted proteins involved in ribosome biogenesis. Taken together, our data reveal an unsuspected function for the Pf1-associated chromatin complex in the ribosomal biogenesis and senescence pathways.
authors.affiliation: New York University School of Medicine, New York, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Graveline
authors.affiliation: New York University School of Medicine, New York, New York, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Marcinkiewicz
authors.affiliation: New York University School of Medicine, New York, New York, USA.
authors.forename: Seyun
authors.initials: S
authors.lastname: Choi
authors.affiliation: Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
authors.forename: Marilène
authors.initials: M
authors.lastname: Paquet
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.affiliation: New York University School of Medicine, New York, New York, USA gregory.david@nyumc.org.
authors.forename: Gregory
authors.initials: G
authors.lastname: David
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism*; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D047108:Embryonic Development; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D063990:Gene Ontology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D001678:Organelle Biogenesis; D011247:Pregnancy; D011485:Protein Binding; D060066:Protein Interaction Maps; D040901:Proteomics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics; D012097:Repressor Proteins; D012270:Ribosomes / Q000378:metabolism
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D018398:Homeodomain Proteins; C000621116:Phf12 protein, mouse; D012335:RNA, Ribosomal; D012097:Repressor Proteins
keywords: Pf1; nucleolus; ribosome; senescence; transcription