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The human pre-replication complex is an open complex
Cell ( IF 45.5 ) Pub Date : 2023-01-05 , DOI: 10.1016/j.cell.2022.12.008
Jian Li 1 , Jiangqing Dong 2 , Weitao Wang 3 , Daqi Yu 2 , Xinyu Fan 1 , Yan Chit Hui 1 , Clare S K Lee 1 , Wai Hei Lam 1 , Nathan Alary 3 , Yang Yang 4 , Yingyi Zhang 5 , Qian Zhao 4 , Chun-Long Chen 3 , Bik-Kwoon Tye 6 , Shangyu Dang 7 , Yuanliang Zhai 1
Affiliation  

In eukaryotes, DNA replication initiation requires assembly and activation of the minichromosome maintenance (MCM) 2–7 double hexamer (DH) to melt origin DNA strands. However, the mechanism for this initial melting is unknown. Here, we report a 2.59-Å cryo-electron microscopy structure of the human MCM-DH (hMCM-DH), also known as the pre-replication complex. In this structure, the hMCM-DH with a constricted central channel untwists and stretches the DNA strands such that almost a half turn of the bound duplex DNA is distorted with 1 base pair completely separated, generating an initial open structure (IOS) at the hexamer junction. Disturbing the IOS inhibits DH formation and replication initiation. Mapping of hMCM-DH footprints indicates that IOSs are distributed across the genome in large clusters aligning well with initiation zones designed for stochastic origin firing. This work unravels an intrinsic mechanism that couples DH formation with initial DNA melting to license replication initiation in human cells.

中文翻译:


人类复制前复合体是一个开放的复合体



在真核生物中,DNA 复制起始需要组装和激活微型染色体维持 (MCM) 2-7 双六聚体 (DH),以熔化原始 DNA 链。然而,这种初始熔化的机制尚不清楚。在这里,我们报告了人类 MCM-DH (hMCM-DH)(也称为复制前复合体)的 2.59-Å 冷冻电子显微镜结构。在此结构中,具有收缩中央通道的 hMCM-DH 解开并拉伸 DNA 链,使得结合的双链 DNA 几乎半圈扭曲,1 个碱基对完全分离,在六聚体处产生初始开放结构 (IOS)交界处。干扰 IOS 会抑制 DH 形成和复制启动。 hMCM-DH 足迹的映射表明,IOS 以大簇的形式分布在整个基因组中,与设计用于随机起源激发的起始区很好地对齐。这项工作揭示了一种内在机制,该机制将 DH 形成与初始 DNA 解链结合起来,以许可人类细胞中的复制启动。
更新日期:2023-01-05
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