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Nature:复旦徐彦辉发现白血病发生关键蛋白工作机制

摘要 : 复旦大学生物医学研究院徐彦辉课题组,首次发现人体内一种名叫“DNMT3A”的蛋白酶在抑制状态和激活状态下的三维晶体结构,并成功揭示了“DNMT3A”蛋白酶在人体基因DNA上精确建立甲基化修饰的机制。相关成果12日在线发表于《自然》杂志。

 

复旦大学生物医学研究院徐彦辉课题组,首次发现人体内一种名叫“DNMT3A”的蛋白酶在抑制状态和激活状态下的三维晶体结构,并成功揭示了“DNMT3A”蛋白酶在人体基因DNA上精确建立甲基化修饰的机制。相关成果12日在线发表于《自然》杂志。

据了解,人体基因组DNA是生命遗传信息的基本载体,而生命延续和繁衍需要DNA上的一种甲基化修饰。“DNMT3A”是一种存在于人体内的蛋白酶,具有在DNA基因上建立甲基化修饰的特殊本领。

临床研究发现,在急性骨髓性白血病患者中,“DNMT3A”蛋白酶基因经常是突变的,而且这种携带基因突变的患者染病后往往预后更差。长期以来,各国科学家虽然知道“DNMT3A”突变与癌症发生有关,但“DNMT3A”是如何在DNA基因组上精确建立甲基化修饰的,一直是研究的难点。

徐彦辉课题组运用一种可把纳米级生物大分子(如蛋白质、DNA等放大10万倍才有米粒大小)清晰成像的X射线晶体学研究方法,经过4年多的不懈探索,终于破解了这一难题。

相关专家表示,该研究首次从分子水平上揭示了“DNMT3A”活性调控机制,丰富了对DNA甲基化建立机制的认识,为今后设计“DNMT3A”蛋白酶活性调控药物用于治疗白血病等打下了坚实的基础。

原文标题:Structural insight into autoinhibition and histone H3-induced activation of DNMT3A

原文摘要:DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance1, 2, 3, 4, 5. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B6, 7, 8, and the methylation patterns vary with developmental stages and cell types9, 10, 11, 12. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a13. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation14. The ATRX–DNMT3–DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0)15, 16, 17. The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro17, 18, wheras the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A–DNMT3L (autoinhibitory form) and DNMT3A–DNMT3L-H3 (active form) complexes at 3.82 and 2.90 ? resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD–CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome9, 10, 19, 20. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.

原文地址:http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13899.html

来源: Nature 浏览次数:95

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