NEIL3グリコシラーゼによるDNAインターストランドクロスリンクの複製依存解鎖
Daniel R Semlow1, Jieqiong Zhang1, Magda Budzowska1
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Cell
|October 4, 2016
まとめ
脊椎動物における新しいDNA修復経路は,切断とは無関係にDNAグリコシラーゼNEIL3を用いて二重鎖断裂 (DSB) を回避する.
科学分野:
- 分子生物学
- DNA 修復 メカニズム
- ユカリオット細胞生物学
背景:
- ユカリオットDNAの鎖間クロスリンク (ICL) 修復には通常,核分解の切断が含まれます.
- 脊椎動物におけるICLとの複製フォークの衝突は,FANCI-FANCD2依存の解き放たれと二重鎖断裂 (DSB) の形成を誘発する.
研究 の 目的:
- 脊椎動物における代替複製結合ICL修復経路を調査する.
- 切断とDSB中間をバイパスするICLの解き放つメカニズムを特定する.
主な方法:
- クセノプスの卵のエキスを細胞なしのシステム研究に使用した.
- 切断に依存する経路と独立した経路を含むICLの解き放つメカニズムを調査した.
- ICLの修復におけるNEIL3とFANCI-FANCD2の役割を評価した.
主要な成果:
- 切断やFANCI-FANCD2を必要としない新しいICL修復経路がXenopus卵エキスで特定されました.
- DNAグリコシラゼNEIL3がN-グリコシル結合を割ってICLを解除し,プソラレンと低位部位ICLの主なメカニズムとして機能することを実証した.
- NEIL3-mediated cleavageがブロックされた場合,ICLの解き放たれはFANCI-FANCD2-依存切断を経由する.
結論:
- 脊椎動物には,NEIL3によって媒介される切断独立のICL解き放つメカニズムが存在する.
- このNEIL3に依存する経路は,研究された細胞フリーシステムにおける好ましいICL修復経路であり,DSBの形成を避けます.
- この発見は,ゲノム安定性とがん治療に意味を持つ DNA インターストランド・クロスリンクの解消のための新しい戦略を明らかにしています.
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