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1. Where and when to start: Regulating DNA replication origin activity in eukaryotic genomes

Author

Clare S.K. Lee, Matthias Weiβ, and Stephan Hamperl

Subjects
3D Genome Organization, chromatin structure, DNA replication, origin clustering, origins of replication, replication timing, Genetics, QH426-470, Cytology, QH573-671
Abstract

ABSTRACTIn eukaryotic genomes, hundreds to thousands of potential start sites of DNA replication named origins are dispersed across each of the linear chromosomes. During S-phase, only a subset of origins is selected in a stochastic manner to assemble bidirectional replication forks and initiate DNA synthesis. Despite substantial progress in our understanding of this complex process, a comprehensive ‘identity code’ that defines origins based on specific nucleotide sequences, DNA structural features, the local chromatin environment, or 3D genome architecture is still missing. In this article, we review the genetic and epigenetic features of replication origins in yeast and metazoan chromosomes and highlight recent insights into how this flexibility in origin usage contributes to nuclear organization, cell growth, differentiation, and genome stability.

Published
2023
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2. The human pre-replication complex is an open complex

Author

Jian Li, Jiangqing Dong, Weitao Wang, Daqi Yu, Xinyu Fan, Yan Chit Hui, Clare S.K. Lee, Wai Hei Lam, Nathan Alary, Yang Yang, Yingyi Zhang, Qian Zhao, Chun-Long Chen, Bik-Kwoon Tye, Shangyu Dang, Yuanliang Zhai, Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), Harvard University, Department of Engineering Mechanics, Zhejiang University, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The University of Hong Kong (HKU), This work was supported by the Research Grants Council (RGC) of Hong Kong (GRF16103918, GRF17112119, GRF17101720, GRF17119022, C7028- 19GF, and C7009-20GF to Y. Zhai., ECS26101919, GRF16103321, C7009- 20GF, and C6001-21EF to S.D.). S.D. acknowledges support from Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou) (SMSEGL20SC01-L), Guangdong Basic and Applied Basic Research Founda- tion (2021A1515012460), and Shenzhen Special Fund for Local Science and Technology Development Guided by Central Government (2021Szvup140). J.D. and D.Y. are supported by LKS fellowships. Work of CLC lab is supported by the YPI program of I. Curie, the ATIP-Avenir program from Centre National de la Recherche Scientifique (CNRS) and Plan Cancer (grant number ATIP/ AVENIR: no. 18CT014-00), the Agence Nationale de la Recherche (ANR) (grant number ReDeFINe-19-CE12-0016-02, TELOCHROM-19-CE12-0020-02), and and Institut National Du Cancer (INCa) (grant number PLBIO19-076). W.W. was supported by a COFUND IC-3i International PhD fellowship.

Subjects
initial DNA melting, replication licensing, [SDV]Life Sciences [q-bio], human MCM2–7 complex, origin firing, DNA replication initiation, General Biochemistry, Genetics and Molecular Biology, pre-RC
Abstract

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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