title: Histone H3 Lysine 9 Acetylation Obstructs ATM Activation and Promotes Ionizing Radiation Sensitivity in Normal Stem Cells.
abstract: 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.
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, Saint Louis, MO 63108, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Meyer
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, Saint Louis, MO 63108, USA.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Fabbrizi
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, Saint Louis, MO 63108, USA.
authors.forename: Suyash
authors.initials: S
authors.lastname: Raj
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, Saint Louis, MO 63108, USA.
authors.forename: Cheri L
authors.initials: CL
authors.lastname: Zobel
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, Saint Louis, MO 63108, USA; Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63108, USA.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, Saint Louis, MO 63108, USA; Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63108, USA. Electronic address: sharma@wustl.edu.
authors.forename: Girdhar G
authors.initials: GG
authors.lastname: Sharma
mesh_terms: D000107:Acetylation; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D053960:DNA Breaks / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000528:radiation effects*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism / Q000528:radiation effects; D011836:Radiation Tolerance / Q000528:radiation effects; D011839:Radiation, Ionizing; D015854:Up-Regulation / Q000235:genetics / Q000528:radiation effects
chemical_list: D006657:Histones; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D008239:Lysine
keywords: ATM; DNA damage response; H3K9ac; H3K9me3; MOZ; epigenetic; histone acetylation; histone methylation; radioprotection; stem cells