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.

Integrative proteomic analysis reveals reprograming tumor necrosis factor signaling in epithelial mesenchymal transition

“…HMGA2 Ser 44 is within the CDK2 kinase substrate motif[60] and Ser 102 is within the ATM kinase substrate motif. Recent studies indicate that HMGA2 can be phosphorylated by ATM, and TGFβ1-induced transcription requires the interplay between HMGA2, ATM and H2AX phosphorylation [61, 62], implying that ATM kinase may play a role in regulating EMT through HMGA2. We also observed the upregulation of phosphorylation of Ser 73 of transcription factor AP1/c-JUN in EMT-hSAECs.…”

MicroRNA-3196 is inhibited by H2AX phosphorylation and attenuates lung cancer cell apoptosis by downregulating PUMA

“…γH2AX induces changes of chromatin that inhibit the assembly of transcription complexes without heterochromatin formation [28]. In addition, recent studies showed that γH2AX is required for high mobility group protein-mediated transcription [29]. Here, we showed that γH2AX could bind to the promoter of miR-3196 and regulate the expression of the apoptotic protein PUMA through miR-3196.…”

DNA damage and gene transcription: accident or necessity?

“…In a recently published study in Cell Research, Singh and collaborators [6] provide further evidence supporting a connection between transcription and DNA repair in the context of the TGFβ1 signaling during epithelial-mesenchymal transition (EMT). The authors use a combination of proteomics-based interactome analysis, ChiP-seq and expression microarrays to propose a novel mechanism of transcriptional activation, which requires HMGA2 and the well-established DNA damage marker H2AX phosphorylated by ATM at S139 (γ-H2AX) (Figure 1).…”