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MCM2-7 加载依赖性 ORC 释放确保了全基因组起始许可。

MCM2-7 loading-dependent ORC release ensures genome-wide origin licensing.

机构信息

DNA Replication Group, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom.

Institute of Molecular Biology (IMB) gGmbH, Ackermannweg 4, Mainz, Germany.

出版信息

Nat Commun. 2024 Aug 24;15(1):7306. doi: 10.1038/s41467-024-51538-9.

DOI:10.1038/s41467-024-51538-9
PMID:39181881
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11344781/
Abstract

Origin recognition complex (ORC)-dependent loading of the replicative helicase MCM2-7 onto replication origins in G1-phase forms the basis of replication fork establishment in S-phase. However, how ORC and MCM2-7 facilitate genome-wide DNA licensing is not fully understood. Mapping the molecular footprints of budding yeast ORC and MCM2-7 genome-wide, we discovered that MCM2-7 loading is associated with ORC release from origins and redistribution to non-origin sites. Our bioinformatic analysis revealed that origins are compact units, where a single MCM2-7 double hexamer blocks repetitive loading through steric ORC binding site occlusion. Analyses of A-elements and an improved B2-element consensus motif uncovered that DNA shape, DNA flexibility, and the correct, face-to-face spacing of the two DNA elements are hallmarks of ORC-binding and efficient helicase loading sites. Thus, our work identified fundamental principles for MCM2-7 helicase loading that explain how origin licensing is realised across the genome.

摘要

复制起始复合物（ORC）依赖性加载复制解旋酶 MCM2-7 到 G1 期的复制起始点，为 S 期的复制叉建立奠定了基础。然而，ORC 和 MCM2-7 如何促进全基因组 DNA 的许可尚不完全清楚。通过对芽殖酵母 ORC 和 MCM2-7 的全基因组进行分子足迹作图，我们发现 MCM2-7 的加载与 ORC 从起始点的释放和再分配到非起始点有关。我们的生物信息学分析表明，起始点是紧凑的单位，其中单个 MCM2-7 双六聚体通过空间位阻 ORC 结合位点阻塞来阻止重复加载。对 A 元件和改进的 B2 元件共有序列模体的分析表明，DNA 形状、DNA 灵活性以及两个 DNA 元件的正确、面对面间隔是 ORC 结合和高效解旋酶加载位点的标志。因此，我们的工作确定了 MCM2-7 解旋酶加载的基本原理，解释了如何在整个基因组中实现起始点许可。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b24/11344781/405e663921f0/41467_2024_51538_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b24/11344781/db37259d2f44/41467_2024_51538_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b24/11344781/405e663921f0/41467_2024_51538_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b24/11344781/70b1e847ff61/41467_2024_51538_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b24/11344781/7ade088fc1b7/41467_2024_51538_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b24/11344781/c553b47df213/41467_2024_51538_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b24/11344781/04e267d58c8b/41467_2024_51538_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b24/11344781/db37259d2f44/41467_2024_51538_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b24/11344781/405e663921f0/41467_2024_51538_Fig7_HTML.jpg

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本文引用的文献

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Proc Natl Acad Sci U S A. 2023 Jul 25;120(30):e2305556120. doi: 10.1073/pnas.2305556120. Epub 2023 Jul 18.
2
A helicase-tethered ORC flip enables bidirectional helicase loading.一种与解旋酶相连的 ORC 翻转可实现双向解旋酶加载。
Elife. 2021 Dec 9;10:e74282. doi: 10.7554/eLife.74282.
3
Chromosomal Mcm2-7 distribution and the genome replication program in species from yeast to humans.
Genes Dev. 2025 Mar 3;39(5-6):304-324. doi: 10.1101/gad.352227.124.
从酵母到人等物种中的染色体 Mcm2-7 分布和基因组复制程序。
PLoS Genet. 2021 Sep 2;17(9):e1009714. doi: 10.1371/journal.pgen.1009714. eCollection 2021 Sep.
4
Accurate modeling of DNA conformational flexibility by a multivariate Ising model.通过多元伊辛模型准确模拟 DNA 构象灵活性。
Proc Natl Acad Sci U S A. 2021 Apr 13;118(15). doi: 10.1073/pnas.2021263118.
5
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