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.

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

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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.

RNAs coordinate nuclear envelope assembly and DNA replication through ELYS recruitment to chromatin.

Aze A, Fragkos M, Bocquet S, Cau J, Méchali M

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.

DNA replication origin activation in space and time

Fragkos M, Ganier O, Coulombe P, Méchali M

MCM9 Is Required for Mammalian DNA Mismatch Repair

Traver S, Coulombe P, Peiffer I, Hutchins JR, 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.

Proteomic data on the nuclear interactome of human MCM9

Hutchins JR, Traver S, Coulombe P, Peiffer I, Kitzmann M, Latreille D, Méchali M.

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.

Genetic and epigenetic determinants of DNA replication origins, position and activation

Méchali M, Yoshida K, Coulombe P, Pasero P.

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

New insights into replication origin characteristics in metazoans.

Cayrou C, Coulombe P, Puy A, Rialle S, Kaplan N, Segal E, 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.

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.

Genome-scale identification of active DNA replication origins

Cayrou C, Grégoire D, Coulombe P, Danis E, Méchali M

Methods in DNA replication

Mechali, 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.

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

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.

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.

A Topoisomerase II-dependent mechanism for resetting replicons at the S-M phase transition

Cuvier, O., Stanojcic, S., Lemaitre, JM., 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.

MCM9 binds Cdt1 and is required for the assembly of prereplication complexes.

Lutzmann M, Méchali M.

Replication, development and totipotency

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

DNA replication origins, Development, and Cancer

Méchali, M.

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.

MCM proteins and DNA replication.

Maiorano D, Lutzmann M, Mechali M.

A Cdt1-geminin complex licenses chromatin for DNA replication and prevents rereplication during S phase in Xenopus.

Lutzmann M, Maiorano D, Mechali M.

DNA replication during animal development and its relevance to gene expression

Grégoire, D., and Méchali, 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.

Recombinant Cdt1 induces rereplication of G2 nuclei in Xenopus egg extracts

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

Mitotic remodeling of the replicon.

Lemaitre, J-M., Danis, E., Vassetzky, Y., Pasero, P., and Mechali, M.

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

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

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.

Specification of a DNA replication origin by a transcription complex.

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

Sleeping policemen for DNA replication

Fisher D., and Marcel Méchali.

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.

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.

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.

Organisation and Dynamics of the Cell Nucleus for DNA Replication.

Lemaitre, J-M., and Méchali, M.

Vertebrate HoxB gene expression requires DNA replication

Fisher, D., and Mechali, M.

DNA replication origins in eukaryotes

Françon, P., and Méchali, M.

Many roads lead to the origin

Maiorano, D., 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.

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.

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.

Chromatin remodelling and DNA replication : from nucleosomes to loop domains

Demeret, C., Vassetzky, Y. and Mchali, M.

A novel cell-free system reveals a mechanism of circular DNA formation from tandem repeats

Cohen, S., and Méchali, M.

DNA replication origins: from sequence specificity to epigenetics

Méchali, M.

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

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

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.

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.

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.

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.

PUBLICATIONS COMMUNES

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

Aze A, Maiorano D
2018 - F1000Res , 7 30228862
Service porteur : Genome Surveillance and Stability

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.
2017 - EMBO J. , 36(18):2726-2741 28778956
Service porteur : Biology of Repetitive Sequences

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.
2015 - Thorax , 70(6):595-7 25616486
Service porteur : Chromatin and cell biology

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

Auziol C, Mechali M, Maiorano D.
2007 - Biochem Biophys Res Commun. , 361, 2, 276-280 17651691
Service porteur : 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.
2005 - Nature , 434: 533-538
Service porteur : Chromatin and cell biology

NASSAR Joëlle
NASSAR Joëlle
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MONTEL Nathalie
MONTEL Nathalie
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CAYROU Christelle
CAYROU Christelle
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NISHIYAMA Atsuya
NISHIYAMA Atsuya
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STANOJCIC Slavica
STANOJCIC Slavica
INRA, Montpellier
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GONZALEZ Laure
GONZALEZ Laure
Helle. Ulrich (Clare Hall Laboratories, UK)
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SAUZAY Pierre
SAUZAY Pierre
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BRODOLIN Konstantin
BRODOLIN Konstantin
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CUCCHI-MOUILLOT Patricia
CUCCHI-MOUILLOT Patricia
Dettachement - UK
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DANIS Etienne
DANIS Etienne
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FRANCON Patricia
FRANCON Patricia
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GONTARZ Renata
GONTARZ Renata
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GREGOIRE Damien
GREGOIRE Damien
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LESIMPLE Pierre
LESIMPLE Pierre
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MAILLET Frederic
MAILLET Frederic
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MORRIS Ann
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PIETTE Jacques
PIETTE Jacques
INSERM EMI 0229 CRLC Val d_Aurelle-Paul Lamarque
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TAULET Nicolas
TAULET Nicolas
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VALENTIN Guillaume
VALENTIN Guillaume
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CHAWAF Mayssa
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VIGNERON Alice
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GLADEL Guillaume
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RODRIGUEZ-MARTINEZ Marta
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TRAVER Sabine
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AGHERBI Hanane
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ARPINON Julie
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FRAGKOS Michail
FRAGKOS Michail
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DESPRAT Romain
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RIALLE Stephanie
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Genetic and epigenetic nature of DNA replication origins

Until recently, only few DNA replication origins had been identified in metazoan cells. In contrast to Saccharomyces cerevisiae, origins in multicellular organisms do not share a common genetic sequence. The availability of new high-throughput methods allowed us to carry out genome-wide analysis of metazoan DNA replication origins. We have now mapped DNA replication origins in mouse embryonic stem cells (ES) cells (Cayrou, Coulombe et al, 2011; Cayrou et al, 2012 ; Cayrou et al, 2015), and also in Drosophila cells (Cayrou, Coulombe et al, 2011). We also mapped replication origins in vivo in C. elegans embryos (Rodriguez et al, 2017).
We found that DNA replication origins are located at precise sites along the genome, but do not share a strict consensus sequence, in contrast to bacterial or S. cerevisiae DNA replication origins. However, we did identify at least one common, repeated consensus element in Drosophila, mouse and human cells that we called OGRE, for Origin G-rich Repeated Element (Cayrou et al, 2012, Cayrou et al, 2015 and Figure 1). This motif is unexpectedly G-rich, in contrast to the AT richness of bacterial and yeast DNA replication origins. We also showed that OGREs can form G quadruplexes (G4s), and that DNA synthesis initiates at a short distance downstream of these elements (Cayrou, Coulombe et al, 2011; Cayrou et al, 2012; Cayrou et al, 2015).

figure 1

Figure 1: OGRE/G4 elements and initiation of DNA replication. OGRE/G4 elements are upstream of the initiation site of DNA synthesis (From Cayrou et al, 2011, 2012, 2015).

We also identified three distinct classes of DNA replication origins, characterized by specific epigenetic marks (Cayrou et al, 2015). These results highlight the plasticity of DNA replication origins according to their chromosomal contexts. Our DNA combing experiments also showed that replication origins are flexible, because only a minor fraction of all potential DNA replication origins is activated at each cell cycle in a given cell, in an apparent stochastic manner. The excess of potential DNA replication origins appears to be an important genome safeguard mechanism to ensure that all sequences are duplicated during the cell cycle. It might also permit to choose the DNA replication origins to be activated according to the pattern of gene expression in a given cell. 

DNA replication origins and cell identity

The arrangement of DNA replication origins could be associated with the organization of chromosomal domains in function of the cell fate and identity, a process linked to development. We provided a first piece of evidence for this model several years ago by demonstrating that DNA replication origins are developmentally regulated in X. laevis (Hyrien and Méchali, 1993 ; Hyrien et al, 1995). We then demonstrated the correlation between the activation of transcription and the specific location of some DNA replication origins (Danis et al, 2004). Moreover, we spotted the coupling between DNA replication and gene expression during the differentiation of pluripotent teratocarcinoma cells into neural cells (Fisher et al, 2003; Gregoire et al, 2006). A similar link between DNA replication origin activity was observed when we mapped DNA replication origins in a living animal, C. Elegans (Rodriguez et al, 2017)
We also demonstrated that the position of DNA replication origins can change in function of the cell identity. Indeed, an extensive reprogramming of DNA replication origin organization occurs when a nucleus from a differentiated cell is exposed to an embryonic context (Lemaitre et al, 2005 ; Ganier et al, 2011). Specifically, when nuclei from differentiated X. laevis cells are incubated with X. laevis egg extracts, their chromosome structure and replication origin organization are remodeled, a process that we demonstrated to be topoisomerase II-dependent (Cuvier et al, 2008). Moreover, this process parallels the transcriptional reprogramming of differentiated nuclei (Ganier et al, 2011). 

DNA replication origin complexes

The third objective of our laboratory is to characterize in greater depth the replication initiation complex, and to understand how DNA replication origins are organized and activated. DNA replication origin recognition and activation occur through the multi-step assembly of several replication factors. The first complex is the pre-replication complex (pre-RC) that permits the assembly of the DNA helicase MCM2-7. ORC is the first known protein to assemble on DNA replication origins, and then serves as a landing pad to assemble CDC6 and CDT1 that are used to recruit the DNA helicase MCM2-7 (Figure 3).

Figure 2

Figure 2: Multi-step assembly of the replication initiation complex (From Fragkos et al, 2015)

We isolated CDT1 using a specific screening method in X. laevis, and demonstrated that it binds to DNA replication origins in an ORC-dependent manner (Maiorano et al, 2000). Further work showed that geminin binds to and inhibits CDT1 (Tada et al, 2001; Maiorano et al, 2004). We then confirmed that the CDT1-geminin complex acts as an ON/OFF switch at DNA replication origins (Lutzmann et al, 2006). Once the helicase is assembled at DNA replication origins, CDT1 is displaced and is no longer required for the further stages of DNA synthesis (Maiorano et al, 2004). If the ratio of CDT1 to geminin is altered, for example by increasing CDT1 level, the cell undergoes another round of replication (Maiorano et al, 2005). To avoid this abnormal re-initiation of replication, CDT1 is degraded during the S-phase of the cell cycle. However, it is synthesized again during the G2 and M phases to prepare initiation in the next cell cycle. We identified a new CDT1 regulatory domain that could be involved in the mechanism to prevent premature DNA replication origin licensing before the next cell cycle (Coulombe et al, 2013). Mutations in this domain increase re-replication and CDT1 oncogenic properties.
Our laboratory is currently using different proteomic approaches to identify and characterize new proteins involved in the regulation of initiation of DNA replication. 

Dissociation of replication complexes

The dissociation of replication complexes is an essential phenomenon that occurs at mitosis entry to allow the clearing of replication complexes from chromosomes. We found that replication protein A (RPA) is not phosphorylated during the whole S phase, but its 34kDa subunit is hyperphosphorylated in mitosis (Francon et al, 2004). RPA34 hyperphosphorylation correlates with its disassembly from chromatin and is critically required for proper chromosome assembly and segregation at mitosis (Cuvier et al, 2006). The ORC complex is also necessary to recruit the kinase CDK1 that phosphorylates RPA34 and allows the disassembly of replication foci before mitosis can occur (Cuvier et al, 2006). We also found that topoisomerase II couples termination of DNA replication with the clearing of the replication complexes at the end of S phase (Cuvier et al, 2008).
The MCM2-7 DNA helicase is another protein complex that must be removed from chromatin after replication. MCM2-7 is a hexamer that forms a ring around DNA, a process regulated in a stepwise manner in X. laevis egg extracts (Maiorano et al, 2000). At the end of replication, this ring should be opened to allow its removal from chromatin. We have shown that MCM-BP, a protein that binds to MCM2-7, allows the disassembly of the MCM2-7 complex in late S phase. MCM-BP inhibition delays mitosis and causes mitotic defects (Nishiyama et al, 2011). We proposed that MCM-BP plays a key role in the mechanism by which pre-RC is cleared from replicated DNA in vertebrate cells. 

Interconnections between DNA replication and DNA repair

We have characterized MCM8 and MCM9, two new MCM family members that are involved in DNA replication and are only present in multicellular organisms. MCM8 is an ATP-dependent DNA helicase that binds to chromatin after the pre-RC assembly and acts at the replication fork (Maiorano et al, 2006). In X. laevis, MCM9 helps CDT1 in the loading of the MCM2-7 helicase at DNA replication origins (Lutzmann et Mechali, 2008). MCM9 might prevent CDT1 inhibition by geminin, which is present in excess in X. laevis egg extracts, during the licensing reaction.
We also generated Mcm8 and Mcm9 knockout mice (Lutzmann et al, 2012), and found that they are viable but sterile. Moreover, Mcm8-/- and Mcm9-/- cells are highly sensitive to replication stress and DNA damage because of defective homologous recombination. Both meiotic and somatic recombination are affected. Consistent with this, we also found that MCM8- and MCM9-defective mice develop ovarian cancer. We also demonstrated that MCM8 and MCM9 form a stable complex in the DNA mismatch repair (MMR) reaction. This complex has a DNA helicase activity that could be involved in the resection of the damaged piece of DNA (Traver et al, 2015). 

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.