SETD1Aの非触媒的機能は,サイクリンKとDNA損傷反応を調節する
Takayuki Hoshii1, Paolo Cifani2, Zhaohui Feng1
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02210, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell
|February 24, 2018
まとめ
SETD1Aタンパク質
科学分野:
- 分子生物学
- 癌 研究
- エピジェネティクス
背景:
- MLL/SETメチルトランスフェラゼは,発達と癌におけるヒストンのメチル化に不可欠である.
- MLL/ SETタンパク質であるSETD1Aは,急性骨髄性白血病 (AML) の細胞生存に不可欠である.
研究 の 目的:
- AML細胞生存におけるSETD1Aの役割を調査する.
- AMLにとって重要なSETD1Aの機能領域を特定する.
- SETD1Aが癌細胞の運命を 影響するメカニズムを探る
主な方法:
- ミュタゲネシス研究
- CRISPR-Cas9ドメインスクリーニング
- DNA損傷反応とアポトーシス経路の分析
- タンパク質とタンパク質の相互作用 (SETD1AとサイクリンK) の評価
主要な成果:
- SETD1Aの酵素SETドメインは,AML細胞の生存に欠かせない.
- SETD1Aにおける新しい"FLOS"ドメインは,AML細胞の生存に不可欠です.
- FLOSドメインの破壊はDNA損傷反応遺伝子を損ない,p53依存アポトーシスを引き起こす.
- FLOSドメインはサイクリンKと結合し,S相における染色体募集とDNA修復遺伝子発現を促進する.
結論:
- AML生存におけるSETD1Aの役割は,ヒストンメチルトランスフェラーゼ活性とは独立している.
- FLOSドメインとサイクリンKの相互作用は,AMLにおけるDNA修復と細胞生存に極めて重要です.
- SETD1AとサイクリンK複合体を標的とした治療は,AMLや他のがんの治療戦略となる可能性があります.
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