School of Chinese Medicine and Department of Biology, Hong Kong Baptist University, Hong Kong, China; Division of Life Science, Center for Cancer Research, and State Key Lab of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China.
Division of Life Science, Center for Cancer Research, and State Key Lab of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China.
Cell Rep. 2020 Mar 10;30(10):3323-3338.e6. doi: 10.1016/j.celrep.2020.02.046.
Eukaryotic DNA replication licensing is a prerequisite for, and plays a role in, regulating genome duplication that occurs exactly once per cell cycle. ORC (origin recognition complex) binds to and marks replication origins throughout the cell cycle and loads other replication-initiation proteins onto replication origins to form pre-replicative complexes (pre-RCs), completing replication licensing. However, how an asymmetric single-heterohexameric ORC structure loads the symmetric MCM (minichromosome maintenance) double hexamers is controversial, and importantly, it remains unknown when and how ORC proteins associate with the newly replicated origins to protect them from invasion by histones. Here, we report an essential and cell-cycle-dependent ORC "dimerization cycle" that plays three fundamental roles in the regulation of DNA replication: providing a symmetric platform to load the symmetric pre-RCs, marking and protecting the nascent sister replication origins for the next licensing, and playing a crucial role to prevent origin re-licensing within the same cell cycle.
真核生物 DNA 复制的许可，是调节细胞周期中基因组精确复制一次的前提和关键。ORC（起始识别复合物）在整个细胞周期中与复制起始点结合并对其进行标记，同时将其他复制起始蛋白加载到复制起始点上，形成预复制复合物（pre-RC），完成复制许可。然而，不对称的单异六聚体 ORC 结构如何加载对称的 MCM（微小染色体维持）双六聚体一直存在争议，重要的是，ORC 蛋白何时以及如何与新复制的起始点结合以防止组蛋白的入侵仍然未知。在这里，我们报告了一个必需的、细胞周期依赖性的 ORC“二聚化循环”，它在 DNA 复制的调控中发挥了三个基本作用：提供一个对称的平台来加载对称的 pre-RC，标记和保护新形成的姐妹复制起始点以备下一轮许可，以及在同一个细胞周期中防止起始点的再次许可。
