Histone H3 Lysine 9 Acetylation Obstructs ATM Activation and Promotes Ionizing Radiation Sensitivity in Normal Stem Cells

• Published in: Stem cell reports 2016-12, Vol.7 (6), p.1013-1022
• Main Authors: Meyer, Barbara, Fabbrizi, Maria Rita, Raj, Suyash, Zobel, Cheri L., Hallahan, Dennis E., Sharma, Girdhar G.
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Ataxia Telangiectasia Mutated Proteins - metabolism; ATM; DNA Breaks - radiation effects; DNA damage response; DNA Repair - radiation effects; Down-Regulation - radiation effects; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - radiation effects; epigenetic; H3K9ac; H3K9me3; histone acetylation; Histone Acetyltransferases - metabolism; histone methylation; Histones - metabolism; Lysine - metabolism; Methylation; Mice, Inbred C57BL; MOZ; Neural Stem Cells - metabolism; Neural Stem Cells - radiation effects; Radiation Tolerance - radiation effects; Radiation, Ionizing; radioprotection; stem cells; Up-Regulation - genetics; Up-Regulation - radiation effects
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2016.11.004

Dynamic spatiotemporal modification of chromatin around DNA damage is vital for efficient DNA repair. Normal stem cells exhibit an attenuated DNA damage response (DDR), inefficient DNA repair, and high radiosensitivity. The impact of unique chromatin characteristics of stem cells in DDR regulation is not yet recognized. We demonstrate that murine embryonic stem cells (ES) display constitutively elevated acetylation of histone H3 lysine 9 (H3K9ac) and low H3K9 tri-methylation (H3K9me3). DNA damage-induced local deacetylation of H3K9 was abrogated in ES along with the subsequent H3K9me3. Depletion of H3K9ac in ES by suppression of monocytic leukemia zinc finger protein (MOZ) acetyltransferase improved ATM activation, DNA repair, diminished irradiation-induced apoptosis, and enhanced clonogenic survival. Simultaneous suppression of the H3K9 methyltransferase Suv39h1 abrogated the radioprotective effect of MOZ inhibition, suggesting that high H3K9ac promoted by MOZ in ES cells obstructs local upregulation of H3K9me3 and contributes to muted DDR and increased radiosensitivity. •Embryonic stem cells show impaired H3K9 deacetylation at DNA DSB sites•Downregulation of MOZ-dependent H3K9ac improves ATM activation in stem cells•MOZ knockdown protects embryonic stem cells from radiation-induced cell death•MOZ suppression-mediated radioprotection is dependent on methyltransferase Suv39h1 H3K9 acetylation is high in stem cells, but requires downregulation at DNA damage sites. Sharma and colleagues show inefficient H3K9 deacetylation and tri-methylation in embryonic stem cells and establish H3K9 acetyltransferase MOZ as a potential therapeutic target to improve ATM activation and stem cell survival after DNA damage induction.