通过NSD甲基转移酶核体H3K36甲基化的分子基础
Wanqiu Li1, Wei Tian2, Gang Yuan3
1Department of Biology, Cryo-EM Centre, Southern University of Science and Technology, Shenzhen, China.
Nature
|December 28, 2020
概括
核受体结合SET域蛋白 (NSD) 家族酶调节色素,并与癌症有关. 这项研究揭示了NSD2和NSD3如何结合核体,激活H3K36甲基化并识别癌症相关突变.
科学领域:
- 生物化学
- 表观遗传学
- 结构生物学
背景情况:
- 核受体结合SET域蛋白 (NSD) 家族酶 (NSD1,NSD2,NSD3) 对染色体调节和瘤生成至关重要.
- NSD酶具有自身抑制的状态,通过核酶结合来缓解,从而使H3 Lys36 (H3K36) 基因组二甲基化.
- 控制核酶激活的精确分子机制在很大程度上仍未被阐明.
研究的目的:
- 阐明NSD2和NSD3被单核细胞识别和激活的分子基础.
- 研究NSD2和NSD3与核细胞结合的结构后果.
- 分析癌症相关突变对NSD2和NSD3功能和细胞效应的影响.
主要方法:
- 用冷电子显微镜 (cryo-EM) 确定与单核细胞结合的NSD2和NSD3的结构.
- 在体外评估催化活性的生物化学测试.
- 细胞测试以评估酶表达和突变对细胞增殖和瘤生长的影响.
主要成果:
- 低温EM结构显示NSD2和NSD3结合在链接区域附近解开DNA,允许催化核插入基因组组和DNA之间.
- 特定的DNA和基因组相互作用残留物网络将酶放置在核体上,解释了H3K36的甲基化特异性.
- 再现的癌症突变改变了NSD与核酶的相互作用,导致催化过活的酶促进癌细胞的增殖和异种移植瘤的生长.
结论:
- 该研究提供了有关NSD2和NSD3如何识别和结合核体的详细分子见解,从而导致H3K36甲基化.
- 与癌症相关的NSD2和NSD3突变导致具有致癌潜力的过度活跃酶.
- 了解这些机制为治疗癌症中NSD家族蛋白提供了潜在的途径.
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