Mechanism of Cross-talk between H2B Ubiquitination and H3 Methylation by Dot1L
Mechanism of Cross-talk between H2B Ubiquitination and H3 Methylation by Dot1L
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DOI：
10.1016/j.cell.2019.02.002
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发表时间：
2019-03-07
期刊：
影响因子：
64.5
通讯作者：
Wolberger, Cynthia
中科院分区：
文献类型：
--
作者：
Worden, Evan J.;Hoffmann, Niklas A.;Wolberger, Cynthia
Dot 1 L对组蛋白H3 K79的甲基化是依赖于H2 B K120（H2 B-Ub）的单泛素化的活跃转录基因的标志，也是从酵母到人类保守的组蛋白修饰串扰的一个例子。我们在这里报告cryo-EM结构的Dot 1 L绑定到泛素化的核小体，显示H2 B-Ub如何刺激Dot 1 L的活性，并揭示了组蛋白H4尾定位Dot 1 L的作用。我们发现，由Dot 1 L和H4尾介导的接触诱导组蛋白H3的球状核心中的构象变化，使K79从一个不可接近的位置重新定向，从而使该侧链插入到活性位点中的一个准备催化的位置。我们的研究提供了一个全面的组蛋白泛素化和甲基化之间的串扰机制，并揭示了组蛋白的结构可塑性，使组蛋白修饰酶有可能进入核小体核心内的残基。
Methylation of histone H3 K79 by Dot1L is a hallmark of actively transcribed genes that depends on mono-ubiquitination of H2B K120 (H2B-Ub) and is an example of histone modification cross-talk that is conserved from yeast to humans. We report here cryo-EM structures of Dot1L bound to ubiquitinated nucleosome that show how H2B-Ub stimulates Dot1L activity and reveal a role for the histone H4 tail in positioning Dot1L. We find that contacts mediated by Dot1L and the H4 tail induce a conformational change in the globular core of histone H3 that reorients K79 from an inaccessible position, thus enabling this side chain to insert into the active site in a position primed for catalysis. Our study provides a comprehensive mechanism of cross-talk between histone ubiquitination and methylation and reveals structural plasticity in histones that makes it possible for histone-modifying enzymes to access residues within the nucleosome core.