香港大学Yuanliang Zhai，北京大学Ning Gao，Qing Li和美国康奈尔大学Bik Kwoon Tye共同合作，近期取得重要工作进展。他们研究提出，亲本组蛋白转移在复制叉处被捕获。相关研究成果2024年3月6日在线发表于《自然》杂志上。

据介绍，在真核生物中，DNA通过核小体压缩成染色质。真核生物基因组的复制必须与染色质中编码的表观基因组的传输相结合。

研究人员报道了与FACT（促进染色质交易）复合物（包括Spt16和Pob3）和一个被驱逐的组蛋白六聚体相关的酵母（酿酒酵母）复制子异构体的冷冻电镜结构。在这些结构中，FACT通过与亲本DNA双链体结合，通过Spt16的中间结构域和酸性羧基末端结构域捕获组蛋白，定位在复制子异构体的前端。由Spt16的羧基末端结构域伴侣的H2A–H2B二聚体稳定地连接到H3–H4四聚体，而空缺的H2A-H2B位点被Mcm2的组蛋白结合结构域占据。

Mcm2组蛋白结合结构域包裹在一个H3–H4二聚体的DNA结合表面，并穿过H3–H4四聚体的四聚化界面延伸到Spt16中间结构域的结合位点，然后变的无序。这种排列使另一个H3–H4二聚体的剩余DNA结合表面暴露于额外的相互作用中，以供进一步处理。Mcm2组蛋白结合结构域及其下游连接区域嵌套在Tof1的顶部，将亲代组蛋白重新定位到复制体前部，以转移到新合成的滞后链DNA。

总之，这一发现为维持表观遗传的复制偶联组蛋白循环机制，提供了至关重要的结构见解。

附：英文原文

Title: Parental histone transfer caught at the replication fork

Author: Li, Ningning, Gao, Yuan, Zhang, Yujie, Yu, Daqi, Lin, Jianwei, Feng, Jianxun, Li, Jian, Xu, Zhichun, Zhang, Yingyi, Dang, Shangyu, Zhou, Keda, Liu, Yang, Li, Xiang David, Tye, Bik Kwoon, Li, Qing, Gao, Ning, Zhai, Yuanliang

Issue&Volume: 2024-03-06

Abstract: In eukaryotes, DNA compacts into chromatin through nucleosomes1,2. Replication of the eukaryotic genome must be coupled to the transmission of the epigenome encoded in the chromatin3,4. Here we report cryo-electron microscopy structures of yeast (Saccharomyces cerevisiae) replisomes associated with the FACT (facilitates chromatin transactions) complex (comprising Spt16 and Pob3) and an evicted histone hexamer. In these structures, FACT is positioned at the front end of the replisome by engaging with the parental DNA duplex to capture the histones through the middle domain and the acidic carboxyl-terminal domain of Spt16. The H2A–H2B dimer chaperoned by the carboxyl-terminal domain of Spt16 is stably tethered to the H3–H4 tetramer, while the vacant H2A–H2B site is occupied by the histone-binding domain of Mcm2. The Mcm2 histone-binding domain wraps around the DNA-binding surface of one H3–H4 dimer and extends across the tetramerization interface of the H3–H4 tetramer to the binding site of Spt16 middle domain before becoming disordered. This arrangement leaves the remaining DNA-binding surface of the other H3–H4 dimer exposed to additional interactions for further processing. The Mcm2 histone-binding domain and its downstream linker region are nested on top of Tof1, relocating the parental histones to the replisome front for transfer to the newly synthesized lagging-strand DNA. Our findings offer crucial structural insights into the mechanism of replication-coupled histone recycling for maintaining epigenetic inheritance.

DOI: 10.1038/s41586-024-07152-2

Source: https://www.nature.com/articles/s41586-024-07152-2