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j.mrgentox.2015.03.012.pdf | 1.08 MB | Adobe PDF | 見る/開く |
タイトル: | Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses. |
著者: | Kobayashi, Junya Saito, Yuichiro Okui, Michiyo Miwa, Noriko Komatsu, Kenshi |
著者名の別形: | 小林, 純也 |
キーワード: | ATM AOA3 Oxidative stress Cell cycle checkpoint Homologous recombination |
発行日: | Apr-2015 |
出版者: | Elsevier B.V. |
誌名: | Mutation research. Genetic toxicology and environmental mutagenesis |
巻: | 782 |
開始ページ: | 42 |
終了ページ: | 50 |
抄録: | Ataxia telangiectasia (AT) is caused by a mutation in the ataxia-telangiectasia-mutated (ATM) gene; the condition is associated with hyper-radiosensitivity, abnormal cell-cycle checkpoints, and genomic instability. AT patients also show cerebellar ataxia, possibly due to reactive oxygen species (ROS) sensitivity in neural cells. The ATM protein is a key regulator of the DNA damage response. Recently, several AT-like disorders have been reported. The genes responsible for them are predicted to encode proteins that interact with ATM in the DNA-damage response. Ataxia with oculomotor apraxia types 1-3 (AOA1, 2, and 3) result in a neurodegenerative and cellular phenotype similar to AT; however, the basis of this phenotypic similarity is unclear. Here, we show that the cells of AOA3 patients display aberrant ATM-dependent phosphorylation and apoptosis following γ-irradiation. The ATM-dependent response to H2O2 treatment was abrogated in AOA3 cells. Furthermore, AOA3 cells had reduced ATM activity. Our results suggest that the attenuated ATM-related response is caused by an increase in endogenous ROS in AOA3 cells. Pretreatment of cells with pyocyanin, which induces endogenous ROS production, abolished the ATM-dependent response. Moreover, AOA3 cells had decreased homologous recombination (HR) activity, and pyocyanin pretreatment reduced HR activity in HeLa cells. These results indicate that excess endogenous ROS represses the ATM-dependent cellular response and HR repair in AOA3 cells. Since the ATM-dependent cell-cycle checkpoint is an important block to carcinogenesis, such inactivation of ATM may lead to tumorigenesis as well as neurodegeneration. |
著作権等: | © 2015. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ The full-text file will be made open to the public on 30 April 2016 in accordance with publisher's 'Terms and Conditions for Self-Archiving'. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 This is not the published version. Please cite only the published version. |
URI: | http://hdl.handle.net/2433/201563 |
DOI(出版社版): | 10.1016/j.mrgentox.2015.03.012 |
PubMed ID: | 25868131 |
出現コレクション: | 学術雑誌掲載論文等 |
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