National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
Mol Cell. 2023 Aug 17;83(16):2884-2895.e7. doi: 10.1016/j.molcel.2023.07.001. Epub 2023 Aug 2.
DNA replication ensures the accurate transmission of genetic information during the cell cycle. Histone variant H2A.Z is crucial for early replication origins licensing and activation in which SUV420H1 preferentially recognizes H2A.Z-nucleosome and deposits H4 lysine 20 dimethylation (H4K20me2) on replication origins. Here, we report the cryo-EM structures of SUV420H1 bound to H2A.Z-nucleosome or H2A-nucleosome and demonstrate that SUV420H1 directly interacts with H4 N-terminal tail, the DNA, and the acidic patch in the nucleosome. The H4 (1-24) forms a lasso-shaped structure that stabilizes the SUV420H1-nucleosome complex and precisely projects the H4K20 residue into the SUV420H1 catalytic center. In vitro and in vivo analyses reveal a crucial role of the SUV420H1 KR loop (residues 214-223), which lies close to the H2A.Z-specific residues D97/S98, in H2A.Z-nucleosome preferential recognition. Together, our findings elucidate how SUV420H1 recognizes nucleosomes to ensure site-specific H4K20me2 modification and provide insights into how SUV420H1 preferentially recognizes H2A.Z nucleosome.
DNA 复制确保了遗传信息在细胞周期中的准确传递。组蛋白变体 H2A.Z 对于早期复制起始点的许可和激活至关重要，在这个过程中，SUV420H1 优先识别 H2A.Z-核小体，并在复制起始点上沉积 H4 赖氨酸 20 二甲基化（H4K20me2）。在这里，我们报告了 SUV420H1 与 H2A.Z-核小体或 H2A-核小体结合的冷冻电镜结构，并证明 SUV420H1 直接与 H4 N 端尾巴、DNA 和核小体中的酸性斑相互作用。H4（1-24）形成套索状结构，稳定 SUV420H1-核小体复合物，并将 H4K20 残基精确地投射到 SUV420H1 催化中心。体外和体内分析揭示了 SUV420H1 KR 环（残基 214-223）的关键作用，该环靠近 H2A.Z 特异性残基 D97/S98，在 H2A.Z-核小体优先识别中发挥作用。总之，我们的研究结果阐明了 SUV420H1 如何识别核小体以确保特定于位置的 H4K20me2 修饰，并为 SUV420H1 如何优先识别 H2A.Z 核小体提供了深入了解。
