英国帝国理工学院David S. Rueda和Dale B. Wigley共同合作，近期取得重要工作进展。他们研究提出，核小体翻转驱动SWR1的动态校对和处理能力。相关研究成果2024年11月6日在线发表于《自然》杂志上。

据介绍，酵母SWR1复合物催化核小体中组蛋白H2A-H2B二聚体与Htz1-H2B二分体的交换。

研究人员使用单分子分析来证明典型酵母核小体中两个H2A-H2B二聚体与Htz1-H2B二分体的两步双交换，并表明双交换可以在不从SWR1复合物中释放核小体的情况下进行。进一步的分析表明，结合的核小体在两种状态之间翻转，每种状态都呈现出不同的面貌，因此组蛋白二聚体也呈现出SWR1的面貌。

当H2A-H2B二聚体被交换时，结合停留时间比Htz1-H2B二聚合体被交换时长。反应中的六聚体中间体以单一方向与SWR1复合物结合，其中“空”位点用于二聚体插入。冷冻电子显微镜分析揭示了不同群体的复合物，显示核小体在不同构象之间“翻转”而不释放，每个核小体都将不同的二聚体置于交换位置，Swc2亚基在这一过程中起着关键作用。

总之，这一研究揭示了双二聚体交换的过程机制，解释了SWR1如何“校对”核小体内的二聚体身份。

附：英文原文

Title: Nucleosome flipping drives kinetic proofreading and processivity by SWR1

Author: Girvan, Paul, Jalal, Adam S. B., McCormack, Elizabeth A., Skehan, Michael T., Knight, Carol L., Wigley, Dale B., Rueda, David S.

Issue&Volume: 2024-11-06

Abstract: The yeast SWR1 complex catalyses the exchange of histone H2A–H2B dimers in nucleosomes, with Htz1–H2B dimers1,2,3. Here we used single-molecule analysis to demonstrate two-step double exchange of the two H2A–H2B dimers in a canonical yeast nucleosome with Htz1–H2B dimers, and showed that double exchange can be processive without release of the nucleosome from the SWR1 complex. Further analysis showed that bound nucleosomes flip between two states, with each presenting a different face, and hence histone dimer, to SWR1. The bound dwell time is longer when an H2A–H2B dimer is presented for exchange than when presented with an Htz1–H2B dimer. A hexasome intermediate in the reaction is bound to the SWR1 complex in a single orientation with the ‘empty’ site presented for dimer insertion. Cryo-electron microscopy analysis revealed different populations of complexes showing nucleosomes caught ‘flipping’ between different conformations without release, each placing a different dimer into position for exchange, with the Swc2 subunit having a key role in this process. Together, the data reveal a processive mechanism for double dimer exchange that explains how SWR1 can ‘proofread’ the dimer identities within nucleosomes.

DOI: 10.1038/s41586-024-08152-y

Source: https://www.nature.com/articles/s41586-024-08152-y