ミトーシス特有のRループ駆動ATR経路は,忠実な染色体分離を促進する

Lilian Kabeche¹, Hai Dang Nguyen¹, Rémi Buisson¹

¹Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.

Science (New York, N.Y.)

|November 25, 2017

まとめ

アタキシア・テランジエクタシア変異とRad3関連 (ATR) キナーゼはミトーシス中の染色体分離を予期せぬ形で調節する. このATR経路は,クロモソームの誤分離と不安定性を防止します.

科学分野:

分子生物学
細胞生物学
遺伝学

背景:

アタキシア・テランジエクタシア変異およびRad3関連 (ATR) キナーゼは,DNA損傷と複製ストレス反応の主要な調節因子である.
DNA修復におけるATRの役割は確立されていますが,ミトーシス中の機能はほとんど未知のままです.

研究の目的:

ミトーシス中のATRキナーゼの予期せぬ役割を調査する.
ATR が染色体分離に影響を与える分子メカニズムを解明する.

主な方法:

ミト細胞におけるATRの急性抑制または分解.
染色体分離ミス,サイクリン依存キナーゼ1 (CDK1) 活性,DNA損傷反応,および非計画的なDNA合成の分析.
セントロメアタンパク質F (CENP-F) との結合とRループとの相互作用によるATR局所化の調査.

主要な成果:

ミトーシス中のATR阻害または分解は,全染色体の誤分離につながった.
この効果はCDK1の活性,DNA損傷反応,または非計画的なDNA合成とは無関係でした.
ATRは,オーロラAとCENP-Fを通じてセントロメアに局所化し,RPAコーティングされたセントロメアRループを巻き込み,Chk1経由でオーロラBを活性化させ,それによって遅れている染色体を防ぐ.

結論:

新しい,ミトーシス特有のATR経路は,Rループによって誘導され,セントロメアで動作する.
この経路は,オーロラBを刺激し,遅れた染色体を防ぐことによって,忠実な染色体分離に不可欠です.
この研究は,細胞分裂中の染色体不安定を抑制する RループとATRの重要な機能を明らかにした.

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