Volume 25, No 7, Jul 2015

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 25 Issue 7, July 2015: 837-850

ORIGINAL ARTICLES

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

Indrabahadur Singh¹, Nihan Ozturk¹, Julio Cordero¹, Aditi Mehta¹, Diya Hasan¹, Claudia Cosentino², Carlos Sebastian², Marcus Krüger³, Mario Looso⁴, Gianni Carraro⁵, Saverio Bellusci^6,9,10, Werner Seeger^7,10, Thomas Braun^8,10, Raul Mostoslavsky² and Guillermo Barreto^1,9,10

¹LOEWE Research Group Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany
²The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02118, USA
³Division of Biomolecular Mass Spectrometry, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany
⁴Group of Bioinformatics, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany
⁵Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
⁶Chair for Lung Matrix Remodeling, Excellence Cluster Cardio Pulmonary System, University Justus Liebig, 35932 Giessen, Germany
⁷Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany
⁸Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany
⁹Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russian Federation
¹⁰Member of the Universities of Giessen and Marburg Lung Center (UGMLC) and the German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL) Correspondence: Guillermo Barreto(guillermo.barreto@mpi-bn.mpg.de)

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.

10.1038/cr.2015.67

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