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Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses

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 thes...

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Autores principales: Jacobs, Keith M., Misri, Sandeep, Meyer, Barbara, Raj, Suyash, Zobel, Cheri L., Sleckman, Barry P., Hallahan, Dennis E., Sharma, Girdhar G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831886/
https://www.ncbi.nlm.nih.gov/pubmed/26941327
http://dx.doi.org/10.1091/mbc.E16-01-0017
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author Jacobs, Keith M.
Misri, Sandeep
Meyer, Barbara
Raj, Suyash
Zobel, Cheri L.
Sleckman, Barry P.
Hallahan, Dennis E.
Sharma, Girdhar G.
author_facet Jacobs, Keith M.
Misri, Sandeep
Meyer, Barbara
Raj, Suyash
Zobel, Cheri L.
Sleckman, Barry P.
Hallahan, Dennis E.
Sharma, Girdhar G.
author_sort Jacobs, Keith M.
collection PubMed
description 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.
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spelling pubmed-48318862016-06-30 Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses Jacobs, Keith M. Misri, Sandeep Meyer, Barbara Raj, Suyash Zobel, Cheri L. Sleckman, Barry P. Hallahan, Dennis E. Sharma, Girdhar G. Mol Biol Cell Articles 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. The American Society for Cell Biology 2016-04-15 /pmc/articles/PMC4831886/ /pubmed/26941327 http://dx.doi.org/10.1091/mbc.E16-01-0017 Text en © 2016 Jacobs et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Jacobs, Keith M.
Misri, Sandeep
Meyer, Barbara
Raj, Suyash
Zobel, Cheri L.
Sleckman, Barry P.
Hallahan, Dennis E.
Sharma, Girdhar G.
Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses
title Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses
title_full Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses
title_fullStr Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses
title_full_unstemmed Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses
title_short Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses
title_sort unique epigenetic influence of h2ax phosphorylation and h3k56 acetylation on normal stem cell radioresponses
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831886/
https://www.ncbi.nlm.nih.gov/pubmed/26941327
http://dx.doi.org/10.1091/mbc.E16-01-0017
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