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Home page > Research Groups > Etienne SCHWOB - DNA Replication, Genome Stability and Cell Identity

Etienne SCHWOB - DNA Replication, Genome Stability and Cell Identity

All eukaryotic cells duplicate their genome using cell-type specific spatio-temporal replication programmes whose nature and functions are still unclear. Our aim is to understand how these programmes are being set-up, how they contribute to cell identity and how their perturbation leads to loss of genome integrity. The specification and firing of replication origins being under tight cell cycle control, we use biological models that depart naturally (stem cells, post-quiescent cells, meiotic cells) or genetically (defined mutants, cancer cell lines) from the standard cell cycle to uncover specific replication patterns and to study their contribution to genome stability and cell identity.

Keywords : Cell cycle, DNA replication, Checkpoints, Chromosome instability, Cancer, Pluripotency, Asymmetric segregation, DNA combing, Yeast, Stem cells.

Chromosome replication is possibly the most complex and influential biological process, yet the precise way it proceeds in eukaryotes is still obscure. It is now estimated that the human genome contains up to 150,000 potential replication origins, whose identification is currently the focus of intense studies. However not all origins are used in every cell cycle or cell type, and the way each cell replicates its genome has profound effect on gene expression patterns, DNA damage and genome integrity. The current view is that chromosomes are organized in Mb-sized domains that are spatially constrained, contain several co-regulated replication origins, and are copied at specific times during S phase. About half of these domains change their timing of replication when cells differentiate or become cancerous . The triggers and mechanisms underlying this switch are not known.

A key but often overlooked property of DNA replication is its inherent stochastic nature, which calls for single-cell or single-molecule analyses. We introduced new methods and assays to assess with unprecedented resolution the dynamics of DNA replication in individual cells.

This led us to reveal i) the key role of G1 cell cycle control and excess replication origin licensing for genome stability in yeast and mammalian cells, ii) the nature of the coupling between S phase and mitosis when replication forks progress normally, iii) the molecular mechanisms underlying chromosome instability in late-replicating cells by showing that cells can enter mitosis with incompletely replicated genomes, iv) the role of centromere early replication for accurate chromosome segregation in yeast and v) the role of cell metabolism and mitochondrial function on nuclear genome stability.

Current work aims at uncovering stem cell-specific replication patterns, their connection to the establishment of pluripotent chromatin and to the asymmetric segregation of epigenetic marks that can determine cell fate.

Institut de Génétique Moléculaire de Montpellier
CNRS-UMR 5535 - 1919, Route de Mende - 34293 Montpellier  Cedex 5
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