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dc.contributor.author | Kobayashi, Junya | en |
dc.contributor.author | Saito, Yuichiro | en |
dc.contributor.author | Okui, Michiyo | en |
dc.contributor.author | Miwa, Noriko | en |
dc.contributor.author | Komatsu, Kenshi | en |
dc.contributor.alternative | 小林, 純也 | ja |
dc.date.accessioned | 2015-11-13T07:05:28Z | - |
dc.date.available | 2015-11-13T07:05:28Z | - |
dc.date.issued | 2015-04 | - |
dc.identifier.issn | 1879-3592 | - |
dc.identifier.uri | http://hdl.handle.net/2433/201563 | - |
dc.description.abstract | 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. | en |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Elsevier B.V. | en |
dc.rights | © 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/ | en |
dc.rights | 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'. | en |
dc.rights | 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。 | ja |
dc.rights | This is not the published version. Please cite only the published version. | en |
dc.subject | ATM | en |
dc.subject | AOA3 | en |
dc.subject | Oxidative stress | en |
dc.subject | Cell cycle checkpoint | en |
dc.subject | Homologous recombination | en |
dc.subject.mesh | Ataxia Telangiectasia Mutated Proteins/metabolism | en |
dc.subject.mesh | Blotting, Western | en |
dc.subject.mesh | Cell Cycle Checkpoints/drug effects | en |
dc.subject.mesh | Cell Cycle Checkpoints/radiation effects | en |
dc.subject.mesh | Cell Cycle Proteins/metabolism | en |
dc.subject.mesh | Cell Line, Transformed | en |
dc.subject.mesh | Cell Line, Tumor | en |
dc.subject.mesh | Cells, Cultured | en |
dc.subject.mesh | DNA Damage | en |
dc.subject.mesh | DNA Repair | en |
dc.subject.mesh | Gamma Rays | en |
dc.subject.mesh | HeLa Cells | en |
dc.subject.mesh | Humans | en |
dc.subject.mesh | Hydrogen Peroxide/pharmacology | en |
dc.subject.mesh | Nuclear Proteins/metabolism | en |
dc.subject.mesh | Oxidants/pharmacology | en |
dc.subject.mesh | Oxidative Stress/drug effects | en |
dc.subject.mesh | Oxidative Stress/radiation effects | en |
dc.subject.mesh | Protein Binding/drug effects | en |
dc.subject.mesh | Protein Binding/radiation effects | en |
dc.subject.mesh | Pyocyanine/pharmacology | en |
dc.subject.mesh | Reactive Oxygen Species/metabolism | en |
dc.subject.mesh | Recombinational DNA Repair/drug effects | en |
dc.subject.mesh | Recombinational DNA Repair/radiation effects | en |
dc.subject.mesh | Spinocerebellar Degenerations/genetics | en |
dc.subject.mesh | Spinocerebellar Degenerations/metabolism | en |
dc.subject.mesh | Spinocerebellar Degenerations/pathology | en |
dc.title | Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses. | en |
dc.type | journal article | - |
dc.type.niitype | Journal Article | - |
dc.identifier.ncid | AA11116545 | - |
dc.identifier.jtitle | Mutation research. Genetic toxicology and environmental mutagenesis | en |
dc.identifier.volume | 782 | - |
dc.identifier.spage | 42 | - |
dc.identifier.epage | 50 | - |
dc.relation.doi | 10.1016/j.mrgentox.2015.03.012 | - |
dc.textversion | author | - |
dc.startdate.bitstreamsavailable | 2016-04-30 | - |
dc.identifier.pmid | 25868131 | - |
dcterms.accessRights | open access | - |
出現コレクション: | 学術雑誌掲載論文等 |
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