A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.

Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decisio...

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Autores principales:	Lili Cao, Hidehiko Kawai, Megumi Sasatani, Daisuke Iizuka, Yuji Masuda, Toshiya Inaba, Keiji Suzuki, Akira Ootsuyama, Toshiyuki Umata, Kenji Kamiya, Fumio Suzuki
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4fc503789a634d4e9abf1730f60ae876
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spelling	oai:doaj.org-article:4fc503789a634d4e9abf1730f60ae8762021-11-25T06:05:54ZA novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.1932-620310.1371/journal.pone.0104279https://doaj.org/article/4fc503789a634d4e9abf1730f60ae8762014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25093836/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decision remain elusive. Here we exposed cultured cells and mice to different doses and dose rates of γ-irradiation, which revealed cell-type-specific sensitivities to chronic, but not acute, γ-irradiation. Among tested cell types, human fibroblasts were associated with the highest levels of growth inhibition in response to chronic γ-irradiation. In this context, fibroblasts exhibited a reversible G1 cell-cycle arrest or an irreversible senescence-like growth arrest, depending on the irradiation dose rate or the rate of DNA damage. Remarkably, when the same dose of γ-irradiation was delivered chronically or acutely, chronic delivery induced considerably more cellular senescence. A similar effect was observed with primary cells isolated from irradiated mice. We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate. Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells. Together these results provide insights into the mechanisms governing cell-fate determination in response to different rates of DNA damage.Lili CaoHidehiko KawaiMegumi SasataniDaisuke IizukaYuji MasudaToshiya InabaKeiji SuzukiAkira OotsuyamaToshiyuki UmataKenji KamiyaFumio SuzukiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 8, p e104279 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lili Cao Hidehiko Kawai Megumi Sasatani Daisuke Iizuka Yuji Masuda Toshiya Inaba Keiji Suzuki Akira Ootsuyama Toshiyuki Umata Kenji Kamiya Fumio Suzuki A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.
description	Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decision remain elusive. Here we exposed cultured cells and mice to different doses and dose rates of γ-irradiation, which revealed cell-type-specific sensitivities to chronic, but not acute, γ-irradiation. Among tested cell types, human fibroblasts were associated with the highest levels of growth inhibition in response to chronic γ-irradiation. In this context, fibroblasts exhibited a reversible G1 cell-cycle arrest or an irreversible senescence-like growth arrest, depending on the irradiation dose rate or the rate of DNA damage. Remarkably, when the same dose of γ-irradiation was delivered chronically or acutely, chronic delivery induced considerably more cellular senescence. A similar effect was observed with primary cells isolated from irradiated mice. We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate. Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells. Together these results provide insights into the mechanisms governing cell-fate determination in response to different rates of DNA damage.
format	article
author	Lili Cao Hidehiko Kawai Megumi Sasatani Daisuke Iizuka Yuji Masuda Toshiya Inaba Keiji Suzuki Akira Ootsuyama Toshiyuki Umata Kenji Kamiya Fumio Suzuki
author_facet	Lili Cao Hidehiko Kawai Megumi Sasatani Daisuke Iizuka Yuji Masuda Toshiya Inaba Keiji Suzuki Akira Ootsuyama Toshiyuki Umata Kenji Kamiya Fumio Suzuki
author_sort	Lili Cao
title	A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.
title_short	A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.
title_full	A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.
title_fullStr	A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.
title_full_unstemmed	A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.
title_sort	novel atm/tp53/p21-mediated checkpoint only activated by chronic γ-irradiation.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/4fc503789a634d4e9abf1730f60ae876
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A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.

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