title: Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses.
abstract: Normal tissue injury resulting from cancer radiotherapy is often associated with diminished regenerative capacity. We examined the relative radiosensitivity of normal stem cell populations compared with non-stem cells within several radiosensitive tissue niches and culture models. We found that these stem cells are highly radiosensitive, in contrast to their isogenic differentiated progeny. Of interest, they also exhibited a uniquely attenuated DNA damage response (DDR) and muted DNA repair. Whereas stem cells exhibit reduced ATM activation and ionizing radiation-induced foci, they display apoptotic pannuclear H2AX-S139 phosphorylation (γH2AX), indicating unique radioresponses. We also observed persistent phosphorylation of H2AX-Y142 along the DNA breaks in stem cells, which promotes apoptosis while inhibiting DDR signaling. In addition, down-regulation of constitutively elevated histone-3 lysine-56 acetylation (H3K56ac) in stem cells significantly decreased their radiosensitivity, restored DDR function, and increased survival, signifying its role as a key contributor to stem cell radiosensitivity. These results establish that unique epigenetic landscapes affect cellular heterogeneity in radiosensitivity and demonstrate the nonubiquitous nature of radiation responses. We thus elucidate novel epigenetic rheostats that promote ionizing radiation hypersensitivity in various normal stem cell populations, identifying potential molecular targets for pharmacological radioprotection of stem cells and hopefully improving the efficacy of future cancer treatment.
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO 63108.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Jacobs
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO 63108.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Misri
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO 63108.
authors.forename: Barbara
authors.initials: B
authors.lastname: Meyer
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO 63108.
authors.forename: Suyash
authors.initials: S
authors.lastname: Raj
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO 63108.
authors.forename: Cheri L
authors.initials: CL
authors.lastname: Zobel
authors.affiliation: Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63108 Department of Pathology, Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63108.
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO 63108 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63108.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO 63108 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63108 sharma@wustl.edu.
authors.forename: Girdhar G
authors.initials: GG
authors.lastname: Sharma
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D015536:Down-Regulation / Q000187:drug effects; D044127:Epigenesis, Genetic; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D017228:Hepatocyte Growth Factor; D006657:Histones; D008239:Lysine; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; C576325:Atm protein, mouse; C475961:gamma-H2AX protein, mouse