SPATA5-SPATA5L1 ATPase複合体は,リプリソームプロテオスタシスを制御し,ゲノムの完全性を確保する

Vidhya Krishnamoorthy¹, Martina Foglizzo², Robert L Dilley¹

¹Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.

Cell

|March 30, 2024

まとめ

新しく特定されたタンパク質複合体55LCCは DNA複製の終結とゲノムの安定性にとって不可欠です複製ストレスや染色体の不安定性を防ぐ.

科学分野:

分子生物学
遺伝学
生物化学

背景:

DNA複製の終結は,VCP/p97によるCMGヘリケースのユビキチン依存の展開に依存する.
複製タンパク質の周回には,CMGの展開を超えたメカニズムが含まれ,他の経路が存在することを示しています.

研究の目的:

複製タンパク質のターンオーバーに関与する新しいタンパク質複合体を特定する.
DNA複製におけるSPATA5-SPATA5L1およびC1orf109-CINP (55LCC) 複合体の構造と機能を明らかにする.

主な方法:

55LCC複合体の分子構造を決定する統合的構造生物学.
ATPaseの活性と基板の分裂を評価する生化学的測定法
複製ストレスとゲノム安定性に対する55LCC欠乏の影響を評価するための細胞研究.

主要な成果:

SPATA5-SPATA5L1とC1orf109-CINPで構成される55LCC複合体は,ATPアゼモーターの頂上にあるユニークなフンネル状の構造を形成する.
LCC欠乏症は,ユビキチン独立のタンパク質毒性,複製ストレス,および重度の染色体不安定性をもたらす.
複合体は,損傷した複製基質のプロテアゼ依存の分裂と結合した複製フォークDNA強化ATPase活性を示しています.

結論:

LCC媒介のプロテオスタシスは,複製フォークの進行とゲノム安定性の維持に不可欠です.
55LCC複合体の機能障害は,ヒトの神経発達障害で観察された病原性変異とのメカニズム的リンクを提供します.

キーワード:

55LCC について AAA+ ATP 酵素 C1orf109 について CINP スパタ5 スパタ5L1 ゲノムの不安定性複製ストレス反応リプリソームの調節/プロテオスタシスデフォルトーゼ

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