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Persistent Amplification of DNA Damage Signal Involved in Replicative Senescence of Normal Human Diploid Fibroblasts


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Title: Persistent Amplification of DNA Damage Signal Involved in Replicative Senescence of Normal Human Diploid Fibroblasts
Authors: Suzuki, Masatoshi / Suzuki, Keiji / Kodama, Seiji / Yamashita, Shunichi / Watanabe, Masami
Issue Date: 2012
Publisher: Hindawi Publishing Corporation
Citation: Oxidative Medicine and Cellular Longevity, 2012, 310534; 2012
Abstract: Foci of phosphorylated histone H2AX and ATM are the surrogate markers of DNA double strand breaks. We previously reported that the residual foci increased their size after irradiation, which amplifies DNA damage signals. Here, we addressed whether amplification of DNA damage signal is involved in replicative senescence of normal human diploid fibroblasts. Large phosphorylated H2AX foci (>1.5 μm diameter) were specifically detected in presenescent cells. The frequency of cells with large foci was well correlated with that of cells positive for senescence-associated β-galactosidase staining. Hypoxic cell culture condition extended replicative life span of normal human fibroblast, and we found that the formation of large foci delayed in those cells. Our immuno-FISH analysis revealed that large foci partially localized at telomeres in senescent cells. Importantly, large foci of phosphorylated H2AX were always colocalized with phosphorylated ATM foci. Furthermore, Ser15-phosphorylated p53 showed colocalization with the large foci. Since the treatment of senescent cells with phosphoinositide 3-kinase inhibitor, wortmannin, suppressed p53 phosphorylation, it is suggested that amplification of DNA damage signaling sustains persistent activation of ATM-p53 pathway, which is essential for replicative senescence.
Keywords: Colocalization / Culture conditions / DNA damages / DNA double strand breaks / Galactosidases / Human diploid fibroblasts / Hypoxic cells / Life span / Normal human fibroblast / Phosphoinositide 3-kinase / Phosphorylated histone / Replicative senescence / Telomeres / Wortmannin
URI: http://hdl.handle.net/10069/30710
ISSN: 19420900
DOI: 10.1155/2012/310534
Rights: © 2012 Masatoshi Suzuki et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/30710

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