Unknown,Transcriptomics,Genomics,Proteomics

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AKT phosphorylates H3-threonine 45 to facilitate termination of gene transcription in response to DNA damage.

ABSTRACT: Purpose: In this study, we show that DNA damage-activated AKT phosphorylates threonine 45 of core histone H3 (H3-T45) Result: By genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis, H3-T45 phosphorylation was distributed throughout DNA damage-responsive gene loci, particularly immediately after the transcription termination site Conclusion: AKT-mediated phosphorylation of H3-T45 regulates the processing of the 3′ end of DNA damage-activated genes to facilitate transcriptional termination MCF10A cells were ChIPed with anti-phosphorylated H3-T45, anti-phosphorylated RNA Pol II-S2 and S5, and anti-H3-K36me3.

ORGANISM(S): Homo sapiens

SUBMITTER: Hong-Duk Youn

PROVIDER: E-GEOD-67699 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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AKT phosphorylates H3-threonine 45 to facilitate termination of gene transcription in response to DNA damage.

Lee Jong-Hyuk JH Kang Byung-Hee BH Jang Hyonchol H Kim Tae Wan TW Choi Jinmi J Kwak Sojung S Han Jungwon J Cho Eun-Jung EJ Youn Hong-Duk HD

Nucleic acids research 20150326 9

Post-translational modifications of core histones affect various cellular processes, primarily through transcription. However, their relationship with the termination of transcription has remained largely unknown. In this study, we show that DNA damage-activated AKT phosphorylates threonine 45 of core histone H3 (H3-T45). By genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis, H3-T45 phosphorylation was distributed throughout DNA damage-responsive gene loci, particularly imm ...[more]

PMID: 25813038

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Project description:The retinoblastoma tumor suppressor protein (Rb) regulates early G1 phase checkpoints, including the DNA damage response, as well as cell cycle exit and differentiation. The widely accepted model of G1 cell cycle progression proposes that cyclin D:Cdk4/6 partially inactivates the Rb tumor suppressor during early G1 phase by progressive multi-phosphorylation, termed hypo-phosphorylation, resulting in release of E2F transcription factors. However, this model remains largely unproven biochemically and the biologically active form(s) of Rb remains unknown. Here we find that Rb is un-phosphorylated in G0 cells and becomes exclusively mono-phosphorylated throughout all of early G1 phase by cyclin D:Cdk4/6. Early G1 phase mono-phosphorylated Rb is composed of 14 independent isoforms that are all targeted by the E1a oncoprotein, but each shows a preferential binding pattern to specific E2F1-4 transcription factors. At the late G1 Restriction Point, cyclin E:Cdk2 inactivates Rb by a quantum hyper-phosphorylation (>12 phosphates/Rb). Cells undergoing a DNA damage response activate cyclin D:Cdk4/6 to generate mono-phosphorylated Rb that regulates global transcription. In contrast, a non-phosphorylatable ?Cdk-Rb allele was non-functional for regulating a DNA damage response, but functional for driving cell cycle exit and differentiation during myogenesis. These observations fundamentally change our understanding of G1 cell cycle progression and show that there is no progressive multi-phosphorylation or hypo-phosphorylation inactivation of Rb during early G1 phase by cyclin D:Cdk4/6. Instead, cyclin D:Cdk4/6 generates functionally active, mono-phosphorylated Rb that is the only Rb isoform present in cells during early G1 phase. Global transcriptional analysis of murine embryonic fibroblasts (MEFs) with conditional deletion of the endogenous RB gene by treatment with cell permeable TAT-Cre. Comparison to unaltered MEFs and MEFs with physiological level of exogenous wildtype or phospho-mutant RB expressed at time of RB gene deletion.

Dataset Information

AKT phosphorylates H3-threonine 45 to facilitate termination of gene transcription in response to DNA damage.

Publications

AKT phosphorylates H3-threonine 45 to facilitate termination of gene transcription in response to DNA damage.

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