随机六聚体
微小染色体维持
生物
原点识别复合体
复制的起源
DNA复制
DNA
半保守复制
细胞生物学
生物物理学
复制前复合体
复制(统计)
真核细胞DNA复制
遗传学
分子生物学
病毒学
作者
Jian Li,Jiangqing Dong,Weitao Wang,Dongke Yu,Xinyu Fan,Yan Chit Hui,Clare S K Lee,Wong Hing Lam,Nathan Alary,Yang Yang,Yingyi Zhang,Qian Zhao,Chun-Long Chen,Bik Kwoon Tye,Shangyu Dang,Yuanliang Zhai
出处
期刊:Cell
[Elsevier]
日期:2023-01-01
卷期号:186 (1): 98-111.e21
被引量:17
标识
DOI:10.1016/j.cell.2022.12.008
摘要
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.
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