title: The PML-associated protein DEK regulates the balance of H3.3 loading on chromatin and is important for telomere integrity.
abstract: Histone variant H3.3 is deposited in chromatin at active sites, telomeres, and pericentric heterochromatin by distinct chaperones, but the mechanisms of regulation and coordination of chaperone-mediated H3.3 loading remain largely unknown. We show here that the chromatin-associated oncoprotein DEK regulates differential HIRA- and DAAX/ATRX-dependent distribution of H3.3 on chromosomes in somatic cells and embryonic stem cells. Live cell imaging studies show that nonnucleosomal H3.3 normally destined to PML nuclear bodies is re-routed to chromatin after depletion of DEK. This results in HIRA-dependent widespread chromatin deposition of H3.3 and H3.3 incorporation in the foci of heterochromatin in a process requiring the DAXX/ATRX complex. In embryonic stem cells, loss of DEK leads to displacement of PML bodies and ATRX from telomeres, redistribution of H3.3 from telomeres to chromosome arms and pericentric heterochromatin, induction of a fragile telomere phenotype, and telomere dysfunction. Our results indicate that DEK is required for proper loading of ATRX and H3.3 on telomeres and for telomeric chromatin architecture. We propose that DEK acts as a "gatekeeper" of chromatin, controlling chromatin integrity by restricting broad access to H3.3 by dedicated chaperones. Our results also suggest that telomere stability relies on mechanisms ensuring proper histone supply and routing.
authors: Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, and Norwegian Center for Stem Cell Research, University of Oslo, 0317 Oslo, Norway;
authors: Kristina
authors: K
authors: Ivanauskiene
authors: Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, and Norwegian Center for Stem Cell Research, University of Oslo, 0317 Oslo, Norway;
authors: Erwan
authors: E
authors: Delbarre
authors: Epigenetics and Chromatin (EpiC) Research, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
authors: James D
authors: JD
authors: McGhie
authors: Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, and Norwegian Center for Stem Cell Research, University of Oslo, 0317 Oslo, Norway;
authors: Thomas
authors: T
authors: Küntziger
authors: Epigenetics and Chromatin (EpiC) Research, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia philippe.collas@medisin.uio.no lee.wong@monash.edu.
authors: Lee H
authors: LH
authors: Wong
authors: Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, and Norwegian Center for Stem Cell Research, University of Oslo, 0317 Oslo, Norway; philippe.collas@medisin.uio.no lee.wong@monash.edu.
authors: Philippe
authors: P
authors: Collas
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D016615:Telomere / Q000378:metabolism*
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C519564:DEK protein, mouse; D004268:DNA-Binding Proteins; C084738:DEK protein, human; D006657:Histones; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins