Loss of Ezh2 function remodels the DNA replication initiation landscape
Paulina Prorok, Faezeh Forouzanfar, Nerea Murugarren, Isabelle Peiffer, Romain Charton, Ildem Akerman, Marcel Méchali.
Replication and Genome Dynamics
At each division, chromosomes should be duplicated and also maintain the memory of the specific transcription programs that were previously established. Initiation of DNA replication is a precisely regulated process that can start at around 100 000 potential sites dispersed along the genome and are called DNA replication origins (Méchali, 2010; Fragkos et al, 2015). Errors in this process can cause loss or gain of genetic material that will lead to genome instability, a hallmark of cancer cells.
An intriguing and essential aspect of DNA replication origins in mammalian cells is their genetic and epigenetic nature, which remains quite elusive. Their characteristics are generally well established in bacterial, viruses, and unicellular eukaryotes, but unraveling their nature in multicellular eukaryotes has been our mains goal along the years. We also wish to understand how their positions along the genome may play a role in the organization of chromosomes in the nucleus and how they could play an essential role in transcriptional controls during development and cell differentiation.
Our laboratory discovered the first genetic consensus element present at drosophila or mouse replication origins and extended its characterization in human cells. We identified an Origin G-rich Repeated Element (OGRE) that could form G quadruplexes (G4). We also found that this element was orientated 150-300 bp upstream of the initiation site and was nucleosome-free. We could further demonstrate its functional importance in mouse cells. Finally, a striking observation of replication origins in mouse or human cells was their concentration at the borders of TAD domains and their disorganization in cancer cells.
Over the years, we have also discovered and/or characterized several proteins involved in DNA replication, including Cdt1, MCM4 (cdc21), MCM8, MCM9, and Obi1.
Our current research is to link DNA replication origins to the organization of chromatin domains in the nucleus.
Publications of the team
A predictable conserved DNA base composition signature defines human core DNA replication origins.
Akerman I, Kasaai B, Bazarova A, Sang PB, Peiffer I, Artufel M, Derelle R, Smith G, Rodriguez-Martinez M, Romano M, Kinet S, Tino P, Theillet C, Taylor N, Ballester B, Méchali M
MCM8- and MCM9 Deficiencies Cause Lifelong Increased Hematopoietic DNA Damage Driving p53- Dependent Myeloid Tumors
Malik Lutzmann, Florence Bernex, Cindy da Costa de Jesus, Dana Hodroj, Caroline Marty, Isabelle Plo, William Vainchenker, Marie Tosolini, Luc Forichon, Caroline Bret, Sophie Queille, Candice Marchive, Jean-Sébastien Hoffmann, Marcel Méchali
OBI1, an ORC ubiquitin ligase promoting DNA replication origin firing
Coulombe P, Nassar J, Peiffer I, Stanojcic S, Sterkers Y, Delamarre A, Bocquet S., Méchali M.
Involvement of G-quadruplex regions in mammalian replication origin activity
Prorok P., Artufel, M., Aze, A., Coulombe, P., Peifer I., Lacroix L., Guédin A., Mergny J.L., Damaschke J., Schepers A. , Cayrou C, Teulade-Fichou MP, Ballester, B., Méchali M.
Metazoan DNA replication origins
Ganier O., Prorok P, Akerman I. , Méchali M.
Recent advances in understanding DNA replication: cell type-specific adaptation of the DNA replication program.
Aze A, Maiorano D
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Genome Surveillance and Stability
RNAs coordinate nuclear envelope assembly and DNA replication through ELYS recruitment to chromatin.
Aze A, Fragkos M, Bocquet S, Cau J, Méchali M
Histone H4K20 tri-methylation at late-firing origins ensures timely heterochromatin replication
Brustel J, Kirstein N, Izard F, Grimaud C, Prorok P, Cayrou C, Schotta G, Abdelsamie AF, Déjardin J, Méchali M, Baldacci G, Sardet C, Cadoret JC, Schepers A, Julien E.
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Biology of Repetitive Sequences
The gastrula transition reorganizes replication origin selection in Caenorhabditis elegans
Rodríguez-Martínez, M., Pinzón, N., Ghommidh, C., Beyne, E., Seitz, H., Cayrou, C., Méchali, M.
Developmental determinants in non-communicable chronic diseases and ageing
Bousquet J, Anto JM, Berkouk K, Gergen P, Pinto Antunes J, Augé P, Camuzat T, Bringer J, Mercier J, Best N, Bourret R, Akdis M, Arshad SH, Bedbrook A, Berr C, Bush A, Cavalli G, Charles MA, Clavel-Chapelon F, Gillman M, Gold DR, Goldberg M, Holloway JW, Iozzo P, Jacquemin S, Jeandel C, Kauffmann F, Keil T, Koppelman GH, Krauss-Etschmann S, Kuh D, Lehmann S, Lodrup Carlsen KC, Maier D, Méchali M, Melén E, Moatti JP, Momas I, Nérin P, Postma DS, Ritchie K, Robine JM, Samolinski B, Siroux V, Slagboom PE, Smit HA, Sunyer J, Valenta R, Van de Perre P, Verdier JM, Vrijheid M, Wickman M, Yiallouros P, Zins M.
Proteomic data on the nuclear interactome of human MCM9
Hutchins JR, Traver S, Coulombe P, Peiffer I, Kitzmann M, Latreille D, Méchali M.
The chromatin environment shapes DNA replication origin organization and defines origin classes
Cayrou C, Ballester B, Peiffer I, Fenouil R, Coulombe P, Andrau JC, van Helden J, Méchali M.
MCM9 Is Required for Mammalian DNA Mismatch Repair
Traver S, Coulombe P, Peiffer I, Hutchins JR, Kitzmann M, Latreille D, Méchali M
DNA replication origin activation in space and time
Fragkos M, Ganier O, Coulombe P, Méchali M
What's that gene (or protein)? Online resources for exploring functions of genes, transcripts, and proteins
Hutchins JR
DNA Replication Origins
Leonard AC, Méchali M
A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing
Coulombe, P., Grégoire, D., Tsanov, N., and Méchali, M.
Genetic and epigenetic determinants of DNA replication origins, position and activation
Méchali M, Yoshida K, Coulombe P, Pasero P.
Sequential steps in DNA replication are inhibited to ensure reduction of ploidy in meiosis
Hua H, Namdar M, Ganier O, Gregan J, Méchali M, Kearsey SE.
Methods in DNA replication
Mechali, M.
Genome-scale identification of active DNA replication origins
Cayrou C, Grégoire D, Coulombe P, Danis E, Méchali M
MCM8- and MCM9-Deficient Mice Reveal Gametogenesis Defects and Genome Instability Due to Impaired Homologous Recombination
Lutzmann M, Grey C, Traver S, Ganier O, Maya-Mendoza A, Ranisavljevic N, Bernex F, Nishiyama A, Montel N, Gavois E, Forichon L, de Massy B, Méchali M.
DNA replication fading as proliferating cells advance in their commitment to terminal differentiation.
Estefanía MM, Ganier O, Hernández P, Schvartzman JB, Mechali M, Krimer DB.
New insights into replication origin characteristics in metazoans.
Cayrou C, Coulombe P, Puy A, Rialle S, Kaplan N, Segal E, Méchali M.
Synergic reprogramming of mammalian cells by combined exposure to mitotic Xenopus egg extracts and transcription factors.
Ganier O, Bocquet S, Peiffer I, Brochard V, Arnaud P, Puy A, Jouneau A, Feil R, Renard JP, and Méchali M
Genome-scale analysis of metazoan replication origins reveals their organization in specific but flexible sites defined by conserved features.
Cayrou C, Coulombe P, Vigneron A, Stanojcic S, Ganier O, Peiffer I, Rivals E, Puy A, Laurent-Chabalier S, Desprat R, Méchali M.
MCM-BP regulates unloading of the MCM2-7 helicase in late S phase.
Nishiyama A, Frappier L, Méchali M.
Eukaryotic DNA replication origins: many choices for appropriate answers.
Méchali, M.
Programming DNA replication origins and chromosome organization.
Cayrou, C., Coulombe, P., Méchali, M
A DNA replication signature of progression and negative outcome in colorectal cancer
Pillaire, M.J., Selves, J., Gordien, K., Gouraud, P.A., Gentil, C., Danjoux, M., Do, C., Negre, V., Bieth, A., Guimbaud, R., Trouche, D., Pasero, P., Méchali, M., Hoffmann, JS, and Cazaux, C
DNA replication origins: multiple choices and appropriate decisions
Méchali, M.
How to load a replicative helicase onto chromatin: a more and more complex matter during evolution.
Lutzmann, M., Méchali, M.
MCM9 binds Cdt1 and is required for the assembly of prereplication complexes.
Lutzmann M, Méchali M.
In Xenopus egg extracts DNA replication initiates preferentially at or near asymmetric AT sequences.
Stanojcic, S., Lemaitre, JM., Brodolin, K., Danis, E., Mechali, M.
A Topoisomerase II-dependent mechanism for resetting replicons at the S-M phase transition
Cuvier, O., Stanojcic, S., Lemaitre, JM., Méchali, M.
Cdk1 and Cdk2 activity levels determine the efficiency of replication origin firing in Xenopus
Krasinska, L., Besnard, E., Cot, E., Dohet, C., Méchali, M., Lemaitre, JM., Fisher, D.
The cell cycle: now live and in color.
Méchali M, and Lutzmann M.
New cell or new cycle?
Ganier, O. and Mechali, M.
Geminin is cleaved by caspase-3 during apoptosis in Xenopus egg extracts
Auziol C, Mechali M, Maiorano D.
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Genome Surveillance and Stability
DNA replication origins, Development, and Cancer
Méchali, M.
Replication, development and totipotency
Lemaitre, JM., Gregoire, D., Mechali, M.
DNA replication during animal development and its relevance to gene expression
Grégoire, D., and Méchali, M.
A Cdt1-geminin complex licenses chromatin for DNA replication and prevents rereplication during S phase in Xenopus.
Lutzmann M, Maiorano D, Mechali M.
MCM proteins and DNA replication.
Maiorano D, Lutzmann M, Mechali M.
Hox B domain induction silences replication origins within the locus and specifies a single origin at its boundary.
Gregoire, D., Brodolin, K., Mechali, M.
ORC is necessary at the interphase-to-mitosis transition to recruit cdc2 kinase and disassemble RPA foci.
Cuvier O, Lutzmann M, Mechali M.
Recruitment of Drosophila Polycomb Group proteins to chromatin by DSP1
Déjardin, J., Rappailles, A., Cuvier, O., Grimaud, C., Decoville, M., Locker, D., and Cavalli, G.
Mitotic remodeling of the replicon.
Lemaitre, J-M., Danis, E., Vassetzky, Y., Pasero, P., and Mechali, M.
MCM8, a novel DNA helicase which is not required for licensing but functions during processive chromosomal replication in vertebratres.
Maiorano, D., Cuvier, O., Danis, E., and Mechali, M.
Recombinant Cdt1 induces rereplication of G2 nuclei in Xenopus egg extracts
Maiorano, D., Krasinska, L., Lutzmann, M. and Mechali M.
Identification of full genes and proteins of MCM9, a novel, vertebrate-specific member of the MCM2-8 protein family
Lutzmann, M., Maiorano, D., and Méchali, M.
A hypophosphorylated form of RPA34 is a specific component of pre-replication centers.
Françon, P. ; Lemaitre, JM., Dreyer, C. ; Maiorano, D. ; Cuvier, O. and Marcel Méchali.
The regulation of competence to replicate in meiosis by Cdc6 is conserved during evolution.
Lemaitre, JM., Bocquet, S., Terret, ME., Namdar, M., Ait-Ahmed, O., Kearsey, S., Verlhac, MH., and Méchali, M.
Crystal Structure of the Coiled-coil Dimerization Motif of Geminin : Structural and Functional Insights on DNA Replication Regulation.
Thepaut, M., Maiorano, D., Guichou, JF., Auge, MT., Dumas, C., Méchali, M., and Padilla, A.
Sleeping policemen for DNA replication
Fisher D., and Marcel Méchali.
Specification of a DNA replication origin by a transcription complex.
Danis, E., Brodolin, K., Menut, S., Maiorano, D., Girard-Reydet, C. and Marcel Méchali.
DNA replication initiates at domains overlapping with nuclear matrix attachment regions in the xenopus and mouse c-myc promoter.
Girard-Reydet, C., Gregoire, D., Vassetzky, Y., and Marcel Méchali.
Cell cycle regulation of the licensing activity of Cdt1 in Xenopus laevis.
Maiorano, D., Rul, W., and Marcel Mechali
DNA replication origins in eukaryotes
Françon, P., and Méchali, M.
Vertebrate HoxB gene expression requires DNA replication
Fisher, D., and Mechali, M.
Organisation and Dynamics of the Cell Nucleus for DNA Replication.
Lemaitre, J-M., and Méchali, M.
Expression of ISWI and its binding to chromatin during the cell cycle and early development
Demeret, C., Bocquet, S., Lemaître, J-M., Françon, P., and Méchali, M.
Formation of extrachromosomal circles from telomeric DNA in Xenopus laevis
Cohen, S., and Méchali, M.
Competence to replicate in the unfertilized egg is conferred by Cdc6 during meiotic maturation
Lemaître, J-M., Bocquet, S., and Méchali, M.
DNA replication origins: from sequence specificity to epigenetics
Méchali, M.
A novel cell-free system reveals a mechanism of circular DNA formation from tandem repeats
Cohen, S., and Méchali, M.
Chromatin remodelling and DNA replication : from nucleosomes to loop domains
Demeret, C., Vassetzky, Y. and Mchali, M.
Repression of origin assembly in metaphase depends on inhibition of RLF-B/cdt1 by geminin.
Tada, S., Li, A., Maiorano, D., Méchali, M., and Blow, J.
Stepwise Regulated Chromatin Assembly of MCM2-7 Proteins.
Maiorano, D., Lemaître, J.M. and Méchali, M.
Specification of chromatin domains and regulation of replication and transcription during development.
Vassetzky, Y., Lemaitre, J.M. and Méchali, M.
Hsp90 is required for Mos activation and biphasic MAP kinase activation in Xenopus oocytes
Fisher, D.L., Mandart, E. and Dorée, M.
Rearrangement of chromatin domains during development in Xenopus
Vassetzky, Y., Hair, A., and Méchali M.
XCDT1 is required for the assembly of pre-replicative complexes in Xenopus laevis
Maiorano, D., Moreau, J., and Méchali, M.
T-antigen interactions with chromatin and p53 during the cell cycle in extracts from Xenopus eggs.
Vassetzky, Y.S., Tchang, F., Fanning, E. and Méchali, M.
Nuclear import of p53 during Xenopus laevis early development in relation to DNA replication and DNA repair.
Tchang, F. and Méchali, M.
Characterization of xenopus RaIB and its involvment in F-actin control during early development.
Moreau, J., Lebreton, S., Iouzalen, N. and Méchali, M.
DNA replication and chromatin assembly using Xenopus egg or embryos.
Menut, S., Lemaitre, J.M., Hair, A. and Méchali, M.
Initiation of DNA replication in eukaryotes : questioning the origin.
Françon, P., Maiorano, D. and Méchali, M.
Regulated formation of extrachromosomal circurlar DNA molecules during development in Xenopus laevis.
Cohen, S., Menut, S. and Méchali, M.
Dynamics of the genome during early Xenopus laevis development : karyomeres as independent units of replication.
Lemaitre, J.M., Géraud, G. and Méchali, M.
Control of gene expression during Xenopus early development.
Hair, A., Prioleau, M.N., Vassetzki, Y. and Méchali, M.
Evidence for different MCM subcomplexes with differential binding to chromatin in Xenopus.
Coué, M., Amariglio, F., Maiorano, D., Bocquet, S. and Méchali, M.
Thèses et hdr
Characterization of the function of OBI1, an E3 ubiquitin ligase, in DNA replication. 25/10/2019
Defended by Joelle Nassar on 25-10-2019