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

作　　者：Indrabahadur Singh Nihan Ozturk Julio Cordero Aditi Mehta Diya Hasan Claudia Cosentino Carlos Sebastian Marcus Kruger Mario Looso Gianni Carraro Saverio Bellusci Werner Seeger Thomas Braun Raul Mostoslavsky Guillermo Barreto 

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

出　　处：《Cell Research》2015年第7期837-850,共14页细胞研究（英文版）

摘　　要：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 reg- ulation by HMG proteins are poorly understood. Here we decipher the molecular mechanism of transcription regu- lation mediated by the HMG AT-hook 2 protein （HMGA2）. We combined proteomic, ChlP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 （H2AXS139ph; ~/-H2AX） mediated by the protein kinase ataxia telangiectasia mutated （ATM）. Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGFI31 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.

关 键 词：HMGA2 Γ-H2AX TGFΒ1 ATM Gata6 transcription chromatin-associated proteins DNA damage 

分 类 号：Q789[生物学—分子生物学] Q523