ヒストンH3のメチル化ライシン79は53BP1をDNA二重鎖の断裂に標的とする
Yentram Huyen1, Omar Zgheib, Richard A Ditullio
1Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA.
Nature
|November 5, 2004
まとめ
ユカリオット細胞は53BP1タンパク質を通じてDNAの二重鎖断裂 (DSB) を感知する. このタンパク質はLys 79にメチル化ヒストンH3を結合し,染色体構造の変化を通じて間接的にDSBを検出する.
科学分野:
- 分子生物学は分子生物学である.
- 細胞生物学 細胞生物学
- バイオケミストリー バイオケミストリー
背景:
- ユカリオットDNAの二重鎖断裂 (DSB) 検出のメカニズムは完全に理解されていません.
- 53BP1は,DNA損傷のチェックポイント反応に関与する保存タンパク質です.
- DSBセンサーとしての53BP1の役割を理解することは,DNA修復経路を理解するために重要です.
研究 の 目的:
- 53BP1のDSBへの採用の構造的根拠を明らかにする.
- DNA損傷センサーとしての53BP1の機能を媒介する特定の相互作用を特定するために.
- 53BP1のDSBへの局所化におけるヒストンの改変の役割を調査する.
主な方法:
- 53BP1タンデムチューダー領域の構造を決定するX線結晶学.
- 53BP1と改変ヒストンペプチドの相互作用を評価するためのインビトロ結合測定法.
- 遺伝子操作 (DOT1L抑制) で,53BP1の採用への影響を評価する.
主要な成果:
- 53BP1タンデムチューダー領域の構造は,保存された残留物によって形成された深いポケットを明らかにします.
- このドメインは,ポケットを覆う残留物を通して,Lys 79 (H3K79me) にメチル化されたヒストンH3に結合します.
- 53BP1がDSBに集まるには,H3K79のメチル化が必要であり,DOT1Lの抑制は,この集約を阻害する.
- H3K79のメチル化レベルは,DNA損傷で変化しないので,間接的な検出が示唆される.
結論:
- 53BP1は,H3K79me.me.を結合するタンデムチューダードメインを通じてDSBセンサーとして機能し,H3K79me.me.を結合する.
- 53BP1は,H3K79me結合部位を露出する変異した染色体構造を認識することによって,間接的にDSBを感知する可能性がある.
- この発見は,DNA損傷応答経路の初期段階に関する新しい洞察を提供します.
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