在rRNA处理和血液形成中,DNA-PKcs具有KU-依赖的功能
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
概括
依赖DNA的蛋白激酶 (DNA-PK) 在核糖体生物发生和血液细胞发育中具有新的依赖RNA的作用,独立于其DNA修复功能. 这种激酶活性对于rRNA处理和预防骨髓衰竭至关重要.
科学领域:
- 分子生物学
- 细胞生物学
- 血液学
背景情况:
- 由KU和DNA-PKcs组成的DNA依赖蛋白激酶 (DNA-PK) 是经典非同源端结合 (cNHEJ) DNA修复的一个关键因素.
- 已知KU与RNA的相互作用,但其在哺乳动物中的功能意义在很大程度上仍未被探索.
- 之前的研究将cNHEJ缺乏和TP53损失与特定的造血性恶性瘤联系在一起.
研究的目的:
- 调查DNA-PK在DNA修复中的非正规功能.
- 阐明DNA-PK在核糖体RNA (rRNA) 生物发生和血液形成中的作用.
- 确定DNA-PKcs在特定部位的酸化对其细胞功能的影响.
主要方法:
- 使用表达酶死DNA-PKc的小鼠模型,具有和没有TP53.
- 研究了在T2609和S2056中阻断DNA- PKcs酸化的效果.
- 检查了DNA- PK局部化,RNA结合和与rRNA处理机械的共同净化.
主要成果:
- 与其他cNHEJ/ TP53缺乏的小鼠所见的亲B细胞淋巴瘤不同,基因酶死亡的DNA- PKcs与TP53缺乏导致骨髓性疾病.
- 在T2609中抑制DNA- PKcs酸化,但不是S2056,导致18SrRNA处理中的KU依赖性缺陷,蛋白质合成受损和骨髓衰竭.
- DNA-PK与包括U3snoRNA在内的各种细胞RNA结合,并以rRNA依赖的方式定位到核细胞,与小子单元过程组结合.
结论:
- 在核糖体生物发生过程中,DNA-PK具有关键的RNA依赖,cNHEJ独立的功能.
- DNA- PKcs 的激酶活性及其在 T2609 群中的酸化对于这些 rRNA 处理作用至关重要.
- 这些发现揭示了DNA- PK在维持造血干细胞功能和预防骨髓衰竭方面的新角色.
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