title: Nucleotide excision repair-dependent DNA double-strand break formation and ATM signaling activation in mammalian quiescent cells.
abstract: Histone H2A variant H2AX is phosphorylated at Ser(139) in response to DNA double-strand break (DSB) and single-stranded DNA (ssDNA) formation. UV light dominantly induces pyrimidine photodimers, which are removed from the mammalian genome by nucleotide excision repair (NER). We previously reported that in quiescent G0 phase cells, UV induces ATR-mediated H2AX phosphorylation plausibly caused by persistent ssDNA gap intermediates during NER. In this study, we have found that DSB is also generated following UV irradiation in an NER-dependent manner and contributes to an earlier fraction of UV-induced H2AX phosphorylation. The NER-dependent DSB formation activates ATM kinase and triggers the accumulation of its downstream factors, MRE11, NBS1, and MDC1, at UV-damaged sites. Importantly, ATM-deficient cells exhibited enhanced UV sensitivity under quiescent conditions compared with asynchronously growing conditions. Finally, we show that the NER-dependent H2AX phosphorylation is also observed in murine peripheral T lymphocytes, typical nonproliferating quiescent cells in vivo. These results suggest that in vivo quiescent cells may suffer from NER-mediated secondary DNA damage including ssDNA and DSB.
authors.affiliation: From the Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Wakasugi
authors.affiliation: From the Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and.
authors.forename: Takuma
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: From the Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and.
authors.forename: Megumi
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: From the Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nagaoka
authors.affiliation: From the Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and.
authors.forename: Keiko
authors.initials: K
authors.lastname: Inoue
authors.affiliation: From the Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and.
authors.forename: Manabu
authors.initials: M
authors.lastname: Inobe
authors.affiliation: the Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Horibata
authors.affiliation: the Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kiyoji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: From the Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and matsukas@p.kanazawa-u.ac.jp.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Matsunaga
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004260:DNA Repair / Q000528:radiation effects*; D004277:DNA, Single-Stranded / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000528:radiation effects*; D015398:Signal Transduction / Q000528:radiation effects*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C413163:MDC1 protein, human; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000076228:MRE11 Homologue Protein
keywords: Ataxia Telangiectasia; DNA Damage Response; DNA Double-stranded Break; G0 Phase; Genomic Instability; H2A Histone Family, Member X (H2AFX); Nucleotide Excision Repair