NSDメチルトランスフェラーゼによる核体H3K36メチル化の分子基礎
Wanqiu Li1, Wei Tian2, Gang Yuan3
1Department of Biology, Cryo-EM Centre, Southern University of Science and Technology, Shenzhen, China.
Nature
|December 28, 2020
まとめ
核受容体結合SETドメインタンパク質 (NSD) 家族の酵素はクロマチンを調節し,がんと関連しています. この研究は,NSD2とNSD3が核分裂体を結合し,H3K36メチル化を活性化し,がんに関連する変異を特定することを明らかにしています.
科学分野:
- 生物化学
- エピジェネティクス
- 構造生物学
背景:
- 核受容体結合SETドメインタンパク質 (NSD) ファミリー酵素 (NSD1,NSD2,NSD3) は,クロマチンの調節と腫瘍生成に不可欠です.
- NSD酵素は自己抑制状態を有し,核細胞結合によって緩和され,ヒストンH3 Lys36 (H3K36) の二メチル化が可能になる.
- ヌクレオソームによるNSD酵素活性化を制御する正確な分子機構は,大部分が解明されていないままである.
研究 の 目的:
- モノヌクレオソームによるNSD2とNSD3の認識と活性化の分子基盤を解明する.
- NSD2とNSD3が核細胞に結合する構造的影響を調査する.
- NSD2とNSD3の機能と細胞効果に対するがん関連変異の影響を分析する.
主な方法:
- モノヌクレオソームに結合したNSD2およびNSD3の構造を決定するための冷凍電子顕微鏡 (冷凍EM).
- 触媒活性を in vitro で評価するための生化学的測定法
- 細胞増殖と腫瘍増殖に対する酵素発現と突然変異の影響を評価するための細胞検査.
主要な成果:
- Cryo-EM構造は,NSD2とNSD3の結合がリンカー領域の近くのDNAを解き放ち,ヒストンオクタマーとDNAの間の触媒コア挿入を可能にします.
- DNAとヒストンの相互作用する残留物の特定のネットワークは,酵素をヌクレオソームに配置し,H3K36のメチル化特異性を説明する.
- 再発する癌変異はNSDと核細胞の相互作用を変化させ,癌細胞の増殖と異種移植腫瘍の成長を促す触媒的過剰活性の酵素につながります.
結論:
- この研究は,NSD2とNSD3が核胞子を認識し,結合し,H3K36メチル化につながる詳細な分子洞察を提供します.
- NSD2とNSD3の癌に関連した変異は,がんを引き起こす可能性のある過剰活性酵素を引き起こす.
- これらのメカニズムの理解は,がんにおけるNSDファミリーのタンパク質を治療的にターゲットにするための潜在的な機会を提供します.
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