ATMは,リンパ球における染色体破裂の持続と拡散を防ぐ

Elsa Callén¹, Mila Jankovic, Simone Difilippantonio

¹Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1360, USA.

|June 30, 2007

まとめ

リンパ球におけるアタキシア・テランジエクタシア変異 (ATM) キナーゼ欠乏症は,V(D) J再結合中にDNA修復が失敗したため,テロメアが削除された末端につながる. ATM機能を復元すると,これらの不安定な染色体が除去され,ゲノムの安定性が維持されます.

科学分野:

遺伝学遺伝学とは
分子生物学は分子生物学である.
免疫学免疫学とは

背景:

DNAの二重鎖断裂 (DSBs) は,アタキシア-テランジエクタシア変異 (ATM) キナーゼシグナル伝達を誘発する.
ATMキナーゼの活動は,不法なDSB結合を抑制し,細胞サイクルチェックポイントを活性化するために重要である.

研究の目的:

リンパ球におけるゲノム安定性に対するATM欠乏の影響を調査する.
V(D) J再結合中のDNA修復エラーの拡散を防止するATMの役割を決定する.

主な方法:

テロメアが削除された染色体の分析は,ATM欠乏性リンパ球で終わります.
これらの異常染色体のin vivoおよびin vitro安定性評価.
末期に染色体が削除された細胞に対するATM回復効果の評価.

主要な成果:

大量の成熟したATM欠乏性リンパ球は,V(D) J再結合末端結合の欠陥から生じるテロメア欠陥末端を備えている.
これらのRAG-1/2エンドヌクレアゼ依存の削除染色体は,リンパ球内で長期にわたって安定しています.
ATM機能が欠けているリンパ球のATMキナーゼ活性を再生することで,これらの末期に削除された染色体の流行を減らすことができます.

結論:

リンパ球におけるゲノム安定性は,正確なDNA末端結合と,持続的なDSBを防ぐためのチェックポイントの両方を必要とします.
このチェックポイントの故障により,V(D) J再結合で生成されたDNA末端が,後期の染色体損傷による転位に参加することができます.

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