title: High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX.
abstract: The eukaryotic genome is organized into chromatins, the physiological template for DNA-dependent processes including replication, recombination, repair, and transcription. Chromatin-mediated transcription regulation involves DNA methylation, chromatin remodeling, and histone modifications. However, chromatin also contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Although it is known that HMG proteins induce structural changes of chromatin, the processes underlying transcription regulation by HMG proteins are poorly understood. Here we decipher the molecular mechanism of transcription regulation mediated by the HMG AT-hook 2 protein (HMGA2). We combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; γ-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGFβ1 signaling. The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Controlled chromatin opening during transcription may involve intermediates with DNA breaks that may require mechanisms that ensure the integrity of the genome.
authors.affiliation: LOEWE Research Group Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
authors.forename: Indrabahadur
authors.initials: I
authors.lastname: Singh
authors.affiliation: LOEWE Research Group Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
authors.forename: Nihan
authors.initials: N
authors.lastname: Ozturk
authors.affiliation: LOEWE Research Group Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
authors.forename: Julio
authors.initials: J
authors.lastname: Cordero
authors.affiliation: LOEWE Research Group Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
authors.forename: Aditi
authors.initials: A
authors.lastname: Mehta
authors.affiliation: LOEWE Research Group Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
authors.forename: Diya
authors.initials: D
authors.lastname: Hasan
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02118, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cosentino
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02118, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sebastian
authors.affiliation: Division of Biomolecular Mass Spectrometry, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Group of Bioinformatics, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Looso
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Gianni
authors.initials: G
authors.lastname: Carraro
authors.affiliation: 1] Chair for Lung Matrix Remodeling, Excellence Cluster Cardio Pulmonary System, University Justus Liebig, 35932 Giessen, Germany [2] Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russian Federation [3] Member of the Universities of Giessen and Marburg Lung Center (UGMLC) and the German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL).
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
authors.affiliation: 1] Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany [2] Member of the Universities of Giessen and Marburg Lung Center (UGMLC) and the German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL).
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: 1] Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany [2] Member of the Universities of Giessen and Marburg Lung Center (UGMLC) and the German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL).
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02118, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.affiliation: 1] LOEWE Research Group Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany [2] Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russian Federation [3] Member of the Universities of Giessen and Marburg Lung Center (UGMLC) and the German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL).
authors.forename: Guillermo
authors.initials: G
authors.lastname: Barreto
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology; D006609:High Mobility Group Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D006609:High Mobility Group Proteins; D006657:Histones; C468783:H2AX protein, human; C475961:gamma-H2AX protein, mouse