酸化ストレスによるATM活性化
Zhi Guo1, Sergei Kozlov, Martin F Lavin
1Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology (ICMB), University of Texas at Austin, Austin, TX 78712, USA.
Science (New York, N.Y.)
|October 23, 2010
まとめ
酸化は,DNA損傷とは関係なく,アタキア・テランジエクタジア変異 (ATM) タンパク質キナーゼを直接活性化します. この発見は,ATMが人間の細胞における酸化ストレスと反応性酸素種の重要なセンサーであることを明らかにしています.
科学分野:
- バイオケミストリー バイオケミストリー
- 分子生物学は分子生物学である.
- セルラー・シグナリング
背景:
- アタクシア・テランジエクタシア変異 (ATM) タンパク質キナーゼは,DNA損傷反応の重要な調節体であり,主にMre11-Rad50-Nbs1 (MRN) 複合体によるDNA二重鎖断裂 (DSB) によって活性化されます.
- ATM欠乏細胞は,酸化ストレスを含む様々な細胞攻撃に対して過敏感を示し,DSBの修復を超えた役割を示唆する.
研究 の 目的:
- 酸化ストレス下でのATMの直接活性化メカニズムを調査する.
- ATMがDNA二重鎖の断裂とMRN複合体とは無関係に活性化できるかどうかを判断する.
主な方法:
- ATMの活性化と二酸化を検出するための生化学的測定法.
- ATMにおけるクリティカルなシステイン残留物のサイト指向型変異.
- 酸化剤への反応としてATMの活性化を評価するための細胞測定法.
主要な成果:
- 酸化はATMの活性化を直接誘導し,DNADSBとMRN複合体から独立して,二硫化物とクロスリンクされたダイマーを形成します.
- 特定のシステイン残留物の変異により,酸化経路経由でATMの活性化が取り消された.
- この経路は,酸化ストレス条件下で観察されたATM活性化を説明します.
結論:
- ATMは,活性酸素種 (ROS) の直接センサーとして機能します.
- オキシダティブ・モディフィケーションは,ATMの活性化のための新しい,直接的な経路を表しています.
- この発見は,細胞のストレス反応におけるATMの役割の理解を広げています.
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