The human pre-replication complex is an open complex.

Humans Cell Cycle Proteins / metabolism Cryoelectron Microscopy DNA Replication DNA-Binding Proteins / metabolism Minichromosome Maintenance Proteins / metabolism Replication Origin
DNA replication initiation human MCM2–7 complex initial DNA melting origin firing pre-RC replication licensing

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
05 01 2023
Historique:
received: 22 05 2022
revised: 13 10 2022
accepted: 05 12 2022
entrez: 7 1 2023
pubmed: 8 1 2023
medline: 11 1 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2022.12.008 PMID: 36608662
pubmed: 36608662
pii: S0092-8674(22)01521-5
doi: 10.1016/j.cell.2022.12.008
pii:
doi:

Substances chimiques

Cell Cycle Proteins 0
DNA-Binding Proteins 0
Minichromosome Maintenance Proteins EC 3.6.4.12

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

98-111.e21

Informations de copyright

Copyright © 2022 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Jian Li (J)

School of Biological Sciences, The University of Hong Kong, Hong Kong, China.

Jiangqing Dong (J)

Division of Life Science, Center of Systems Biological and Human Health, The Hong Kong University of Science and Technology, Hong Kong, China.

Weitao Wang (W)

Institut Curie, PSL Research University, CNRS UMR3244, Dynamics of Genetic Information, Sorbonne Université, 75005 Paris, France.

Daqi Yu (D)

Division of Life Science, Center of Systems Biological and Human Health, The Hong Kong University of Science and Technology, Hong Kong, China.

Xinyu Fan (X)

School of Biological Sciences, The University of Hong Kong, Hong Kong, China.

Yan Chit Hui (YC)

School of Biological Sciences, The University of Hong Kong, Hong Kong, China.

Clare S K Lee (CSK)

School of Biological Sciences, The University of Hong Kong, Hong Kong, China.

Wai Hei Lam (WH)

School of Biological Sciences, The University of Hong Kong, Hong Kong, China.

Nathan Alary (N)

Institut Curie, PSL Research University, CNRS UMR3244, Dynamics of Genetic Information, Sorbonne Université, 75005 Paris, France.

Yang Yang (Y)

State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, China.

Yingyi Zhang (Y)

Biological Cryo-EM Center, The Hong Kong University of Science and Technology, Hong Kong, China.

Qian Zhao (Q)

State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, China.

Chun-Long Chen (CL)

Institut Curie, PSL Research University, CNRS UMR3244, Dynamics of Genetic Information, Sorbonne Université, 75005 Paris, France. Electronic address: chunlong.chen@curie.fr.

Bik-Kwoon Tye (BK)

Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China; Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY 14853, USA. Electronic address: biktye@ust.hk.

Shangyu Dang (S)

Division of Life Science, Center of Systems Biological and Human Health, The Hong Kong University of Science and Technology, Hong Kong, China; Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China; HKUST-Shenzhen Research Institute, Nanshan, Shenzhen 518057, China. Electronic address: sdang@ust.hk.

Yuanliang Zhai (Y)

School of Biological Sciences, The University of Hong Kong, Hong Kong, China. Electronic address: zhai@hku.hk.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The human pre-replication complex is an open complex.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › The human pre-replication complex is an open complex.
questionsmedicales.fr › Techniques d'investigation › Microscopie électronique › Cryomicroscopie électronique › The human pre-replication complex is an open complex.
questionsmedicales.fr › Phénomènes génétiques › Réplication de l'ADN › The human pre-replication complex is an open complex.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › The human pre-replication complex is an open complex.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines chromosomiques nonhistones › Protéines de maintenance des minichromosomes › The human pre-replication complex is an open complex.
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Réplicon › Origine de réplication › The human pre-replication complex is an open complex.