DNA-PKcsは,rRNA処理と血液形成においてKUに依存する機能を有する
Zhengping Shao1,2, Ryan A Flynn3, Jennifer L Crowe1,4
1Institute for Cancer Genetics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Nature
|February 28, 2020
まとめ
DNA依存タンパク質キナーゼ (DNA-PK) は,DNA修復機能とは独立して,リボソーム生体形成と血液細胞の発達において,新しいRNA依存的役割を果たしている. このキナーゼ活動は,rRNA処理と骨髄不全の予防に不可欠です.
科学分野:
- 分子生物学
- 細胞生物学
- 血液学
背景:
- KUとDNA-PKcsで構成されるDNA依存タンパク質キナーゼ (DNA-PK) は,古典的な非同類末端結合 (cNHEJ) DNA修復の重要な要因である.
- KUとRNAの相互作用は知られているが,哺乳類におけるその機能的意義はほとんど未知のままである.
- 以前の研究では,cNHEJ欠乏症とTP53欠乏症が特定の造血性悪性腫瘍と関連していた.
研究 の 目的:
- DNA-PKの非正規的機能の調査 DNA修復におけるその役割を超えて
- リボソームRNA (rRNA) の生殖と血液形成におけるDNA-PKの役割を明らかにする.
- 特定の部位でのDNA-PKcsのリン酸化が細胞機能に与える影響を決定する.
主な方法:
- TP53 を含むまたは含まないキナーゼデッドDNA- PKc を発現するマウスモデルを使用した.
- T2609とS2056のクラスターでのDNA- PKcsのリン酸化を阻害する効果を調査した.
- DNA-PKの局所化,RNAの結合,およびrRNA処理装置による共浄化について検討した.
主要な成果:
- キナーゼデッドDNA- PKcsは,他のcNHEJ/ TP53欠乏したマウスで見られたプロB細胞リンパ腫とは異なり,TP53欠乏と併合して,骨髄性疾患を引き起こした.
- T2609でのDNA- PKcsのリン酸化抑制は,S2056ではないが,18S rRNA処理のKU依存の欠陥,タンパク質合成の障害,骨髄不全を引き起こした.
- DNA-PKは,U3スノRNAを含む様々な細胞RNAと結合し,rRNAに依存した方法で核細胞に局所化し,小さなサブユニットプロセソームと結合する.
結論:
- DNA-PKは,リボソーム生物生成において,RNAに依存し,cNHEJに依存しない重要な機能を有する.
- DNA- PKcsのキナーゼ活性とそのT2609クラスタでのリン酸化は,これらのrRNA処理の役割に不可欠である.
- これらの発見は,血液形成幹細胞の機能を維持し,骨髄不全を予防するDNA- PKの新たな役割を明らかにしています.
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