Replication and Genome Dynamics

Genome dynamics

The chromatin organization and the plasticity of this organization are essential to development programs and the maintenance of differentiation. At each division, chromosomes should be duplicated and also maintain the memory of the specific transcription programs that have been previously established in the embryo. Our objective is to understand how DNA replication can be integrated to transcriptional controls during development. We also characterize the DNA replication initiation complexes and analyze how epigenetic mechanisms control the organization of chromatin domains for replication.

At each cell division, chromosomes must be duplicated and the memory of the previously established specific transcription programs maintained. DNA replication is a precisely regulated process that starts at dozen of thousands of sites that are 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.

Our objectives are to characterize the genetic and epigenetic nature of DNA replication origins, to understand how they are integrated in chromatin domains and transcriptional programs, and to identify new factors involved in initiation of DNA replication.

Current research

  • We are characterizing DNA  domains are organized for DNA replication.
  • We wish to understand the epigenetic mechanisms leading to the formation of DNA replication initiation complexes.
  • We are also interested in uncovering new factors involved in the regulation of the initiation complex using in vitro systems derived f rom X. laevis eggs and cultured mammalian cells.

We welcome enthusiastic post-doctoral scientists willing to share our interest in these areas.

Marcel MECHALI
Researcher

0434359917
Manon Bouvier
Manon BOUVIER
Technicienne biologiste
IT

0434359919
Nadege Gaborit
Nadege GABORIT
IT

0434359919
Sophie Marchizet
Sophie MARCHIZET
Technicienne biologiste
IT

0434359919
Isabelle Peiffer
Isabelle PEIFFER
IT

0434359919
Romain Charton
Romain CHARTON
Postdoc

0434359919

PUBLICATIONS OF THE TEAM

Replication timing and genetic instability

Marcel Méchali

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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

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Metazoan DNA replication origins

Ganier O., Prorok P, Akerman I. , and 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., Ballester, B., and Méchali, M.

OBI1, an ORC ubiquitin ligase promoting DNA replication origin firing

Coulombe P, Nassar J, Peiffer I, Stanojcic S, Sterkers Y, Delamarre A, Bocquet S. and Méchali M.

Recent advances in understanding DNA replication: cell type-specific adaptation of the DNA replication program.

Aze A, Maiorano D


+ 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.


+ 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.

+ Systemic impact of small regulatory RNAs

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

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.


+ Chromatin and cell biology

What's that gene (or protein)? Online resources for exploring functions of genes, transcripts, and proteins

Hutchins JR

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.

A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing

Coulombe, P., Grégoire, D., Tsanov, N., and Méchali, M.

DNA Replication Origins

Leonard AC, Méchali M

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.

+ Meiosis and recombination

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.

MCM-BP regulates unloading of the MCM2-7 helicase in late S phase.

Nishiyama A, Frappier L, 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.

+ Laboratory of Molecular Virology

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

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

+ Maintenance of genome integrity during DNA replication

Programming DNA replication origins and chromosome organization.

Cayrou, C., Coulombe, P., Méchali, M

Eukaryotic DNA replication origins: many choices for appropriate answers.

Méchali, M.

How to load a replicative helicase onto chromatin: a more and more complex matter during evolution.

Lutzmann, M., Méchali, M.

DNA replication origins: multiple choices and appropriate decisions

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.

New cell or new cycle?

Ganier, O. and Mechali, M.

The cell cycle: now live and in color.

Méchali M, and Lutzmann 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.

Replication, development and totipotency

Lemaitre, JM., Gregoire, D., Mechali, M.

DNA replication origins, Development, and Cancer

Méchali, M.

Geminin is cleaved by caspase-3 during apoptosis in Xenopus egg extracts

Auziol C, Mechali M, Maiorano D.


+ Genome Surveillance and Stability

ORC is necessary at the interphase-to-mitosis transition to recruit cdc2 kinase and disassemble RPA foci.

Cuvier O, 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.

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.

+ Genome Surveillance and Stability

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.

+ Genome Surveillance and Stability

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.


+ Chromatin and cell biology

Recombinant Cdt1 induces rereplication of G2 nuclei in Xenopus egg extracts

Maiorano, D., Krasinska, L., Lutzmann, M. and Mechali M.

+ Genome Surveillance and Stability

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.

+ Genome Surveillance and Stability

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.

+ Genome Surveillance and Stability

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.

+ Meiosis and recombination

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.

+ Genome Surveillance and Stability

Cell cycle regulation of the licensing activity of Cdt1 in Xenopus laevis.

Maiorano, D., Rul, W., and Marcel Mechali

+ Genome Surveillance and Stability

Specification of a DNA replication origin by a transcription complex.

Danis, E., Brodolin, K., Menut, S., Maiorano, D., Girard-Reydet, C. and Marcel Méchali.

+ Genome Surveillance and Stability

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.

Sleeping policemen for DNA replication

Fisher D., and Marcel Méchali.

Organisation and Dynamics of the Cell Nucleus for DNA Replication.

Lemaitre, J-M., and Méchali, M.

DNA replication origins in eukaryotes

Françon, P., and Méchali, M.

Vertebrate HoxB gene expression requires DNA replication

Fisher, D., and Mechali, M.

Competence to replicate in the unfertilized egg is conferred by Cdc6 during meiotic maturation

Lemaître, J-M., Bocquet, S., and Méchali, M.

Formation of extrachromosomal circles from telomeric DNA in Xenopus laevis

Cohen, S., 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.

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.

+ Genome Surveillance and Stability

XCDT1 is required for the assembly of pre-replicative complexes in Xenopus laevis

Maiorano, D., Moreau, J., and Méchali, M.

+ Genome Surveillance and Stability

Rearrangement of chromatin domains during development in Xenopus

Vassetzky, Y., Hair, A., 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.

Specification of chromatin domains and regulation of replication and transcription during development.

Vassetzky, Y., Lemaitre, J.M. and Méchali, M.

Stepwise Regulated Chromatin Assembly of MCM2-7 Proteins.

Maiorano, D., Lemaître, J.M. and Méchali, M.

+ Genome Surveillance and Stability

Regulated formation of extrachromosomal circurlar DNA molecules during development in Xenopus laevis.

Cohen, S., Menut, S. and Méchali, M.

Initiation of DNA replication in eukaryotes : questioning the origin.

Françon, P., Maiorano, D. and Méchali, M.

+ Genome Surveillance and Stability

DNA replication and chromatin assembly using Xenopus egg or embryos.

Menut, S., Lemaitre, J.M., Hair, A. 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.

Nuclear import of p53 during Xenopus laevis early development in relation to DNA replication and DNA repair.

Tchang, F. 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.

Evidence for different MCM subcomplexes with differential binding to chromatin in Xenopus.

Coué, M., Amariglio, F., Maiorano, D., Bocquet, S. and Méchali, M.

+ Genome Surveillance and Stability

Control of gene expression during Xenopus early development.

Hair, A., Prioleau, M.N., Vassetzki, Y. 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.

COULOMBE Philippe
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STANOJCIC Slavica
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INRA, Montpellier
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GONZALEZ Laure
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Helle. Ulrich (Clare Hall Laboratories, UK)
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GREGOIRE Damien
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