High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX
High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX
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DOI：
10.1038/cr.2015.67
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发表时间：
2015-07-01
期刊：
影响因子：
44.1
通讯作者：
Barreto, Guillermo
中科院分区：
文献类型：
--
作者：
Singh, Indrabahadur;Ozturk, Nihan;Barreto, Guillermo
真核生物基因组由染色质组成，染色质是dna依赖过程的生理模板，包括复制、重组、修复和转录。染色质介导的转录调控包括DNA甲基化、染色质重塑和组蛋白修饰。然而，染色质也含有非组蛋白染色质相关蛋白，其中高迁移率组（HMG）蛋白最为丰富。虽然已知HMG蛋白诱导染色质的结构变化，但HMG蛋白转录调控的过程尚不清楚。本研究揭示了HMG AT-hook 2蛋白（HMGA2）介导的转录调控的分子机制。我们结合蛋白质组学、ChIP-seq和转录组学数据表明，hmga2诱导的转录需要组蛋白变体H2AX在S139位点磷酸化（H2AXS139ph; γ -H2AX），由蛋白激酶ataxia毛细血管扩张突变（ATM）介导。此外，我们在TGF β 1信号的背景下证明了该机制的生物学相关性。HMGA2、ATM和H2AX之间的相互作用是一种新的转录起始机制。我们的研究结果将H2AXS139ph与转录联系起来，为这种DNA损伤标记赋予了一种新的功能。转录过程中控制染色质打开可能涉及DNA断裂的中间体，这可能需要确保基因组完整性的机制。
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; gamma-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGF beta 1 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.