Telomeres are key features of linear chromosomes that preserve genome stability and function. Variations in telomere status are critical for cell senescence, stem cell biology, and the development of cancer. Our team investigates in budding and fission yeast how telomeres are replicated and maintained and the cellular responses to telomere erosion. Our current work and projects in yeast focus on the dynamics of telomere repair during replicative senescence and the role of the NPC in processing eroded telomeres and collapsed replication forks. We also study the mechanisms of telomere maintenance during quiescence using fission yeast as model. In addition, we started new programmes aimed to decipher how the p21-driven expression of telomerase in mice at the same time promotes the escape of senescence and deregulates signalling and metabolic pathways. Finally, we investigate the mechanisms of ALT in human cancer of mesenchymal origin.

Set1 is the catalytic subunit of a protein complex called Set1C or COMPASS (for Complex of Proteins Associated with Set1) that mediates H3 methylation at lysine 4 (H3K4). In budding yeast, Set1C and H3K4 methylation have been involved in multiple processes such as transcription, chromosome segregation, transcription termination, DNA replication, and meiotic recombination. Our team has a unique expertise to provide an integrative view of the various functions of the Set1C


In the past years, our lab showed in both yeast that the single-stranded DNA-binding RPA prevents secondary structures to occur at telomeres and thereby facilitates telomerase action at chromosome ends. We uncovered in S. cerevisiae that telomerase can be recruited on the lagging and the leading telomere but that the Mre11-Rad50-Xrs2-dependent resection activity is only required for the telomerase recruitment at the leading telomere. We further reported that Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA at telomeres. Recently, we collaborated with the Ming Lei’s Team (Shanghai Institute of Precision Medecine) in testing in vivo a model of telomerase recruitment based on their outstanding structural insights. In collaboration with the groups of Eric Gilson and Michael Lisby, we did pioneering work to characterize by single cell analysis the telomeric DNA damage response at eroded telomeres. We demonstrated that eroded telomeres relocate during replicative senescence from their nuclear envelope anchor site to the Nuclear pore complex and dissected the mechanism by which eroded are targeted to the NPC. Recently, we investigated telomere maintenance in fission yeast in vegetative cells and during quiescence. We showed that the Stn1-Ten1 complex limits telomerase activity and promotes sub-telomere and telomere replication. In quiescence, we reported that eroded telomeres are highly rearranged during quiescence in telomerase minus cells through a process involving Homologous Recombination and TERRA.


Fission yeast Schizosaccharomyces pombe is a great model for cellular quiescence. Indeed, S. pombe can be experimentally maintained for weeks in quiescence in the absence of nitrogen. We took this opportunity to study the mechanism by which telomeres are maintained during quiescence. Indeed, although telomeres maintenance has been extensively studied in cycling cell, rare studies have been undertaken in quiescent cells. In this context, we investigate the stability of telomeres in quiescent cells, in particular the fate of short telomeres in quiescent cells in the presence and absence of telomerase. We characterize mechanisms of repair and elongation of short telomeres that are specific to post-mitotic cells.


The nuclear pore complex (NPC) are composed of 30 individual nucleoporins to form highly conserved macromolecular structures in the nuclear envelope. Its core function is the nucleo-cytoplasmic transport and RNA export, but several individual nucleoporins have been involved in DNA repair. Hard‐to‐repair DNA lesions, including irreparable double strand breaks (DSBs), eroded telomeres and collapsed replication forks relocate to NPC at which alternative repair pathways take place. We investigate in budding and fission yeast how eroded telomeres and replication forks stalled at telomere repeats are processed and the role of the NPC in promoting telomere repair and fork‐restart.


Our previous results obtained in both yeasts, S cerevisiae and S. pombe, indicate that RPA promotes telomerase activity at chromosome ends. We proposed that RPA prevents the formation of G-quadruplex structures at lagging strand telomeres to promote telomere protein association and facilitate telomerase action at telomeres. Because in both yeasts the action of telomerase is thought to be tightly coupled to the progression of the replication fork, we proposed that the association of RPA to telomerase couples telomere replication by DNA polymerases and telomere elongation by telomerase. Nevertheless, the mechanism by which RPA promotes telomerase action is not fully understood. We further investigate how RPA can promote the action of telomerase. We recently initiated studies aimed to understand the role of RPA in telomere maintenance in humans


A key regulator of cellular arrest in response to telomere shortening and DNA damage is the cyclin-dependent kinase inhibitor p21. p53-dependent upregulation of p21 is thought to be the primary event inducing replicative senescence. We asked whether aging could be delayed by abrogating telomere shortening in senescent cells by expressing telomerase “only when it is needed” and what would be the consequences of this conditional ectopic expression of telomerase. Indeed, previous studies revealed that overexpression of telomerase promotes cell proliferation and inflammation independently of its activity at telomeres. To this purpose, we have created a knock-in mouse model in which a cassette encoding mCherry-2A-mTert (telomerase) has been inserted after the first exon of p21 (p21-mTert mouse). While p21-driven expression of telomerase suppresses senescence in several tissues, we observed unexpected phenotypes associated to this ectopic telomerase expression. Our project aims to understand how the p21-driven expression of telomerase at the same time promotes the escape of senescence and deregulates signalling and metabolic pathways


Osteosarcomas are highly aggressive bone tumours that mainly occur in children and adolescents. Genetically, they are characterized by complex structural and numerical aberrations. Osteosarcomas are known for exhibiting a high frequency of ALT activation. Previous reports showed that ATRX gene mutation and/or loss of protein expression is detectable in only 30% of them. This discrepancy between a high level of ALT and a low proportion of ATRX inactivation led us to the hypothesis that ATRX-mediated ALT inhibition could be overridden in certain conditions. We investigate the mechanisms underlying ALT osteosarcomas.


By the same time as the group of Loraine Pillus (UCSD), we identified SET1 as the Saccharomyces cerevisiae gene encoding the yeast most closely related to SET domain proteins of multicellular organisms. Deletion of SET1 alleviated telomeric position effect, resulted in a mild shortening of telomeres and increased viability after DNA damage of checkpoint sensor mutants. Few years after, it was discovered by several other teams that Set1 was the catalytic subunit of a protein complex called Set1C or COMPASS (for Complex of Proteins Associated with Set1) that mediates H3 methylation at lysine 4 (H3K4). We had then an important contribution in collaboration with Francis Stewart’s Team in defining how each subunit of the Set1C was bound to the docking platform made by the catalytic Set1 subunit. Others and we showed that loss of individual Set1C subunits differentially affects Set1 stability, complex integrity, global H3K4 methylation patterns, and H3K4 methylation along active genes. After having characterized the RNA Recognition Motifs of Set1, we uncovered in collaboration with Jaehoon Kim and Domenico Libri that Set1 directly binds RNA in vitro an in vivo. We discovered that Set1 binding to nascent transcripts is important to define the appropriate topology of Set1C distribution along transcription units and correlates with the efficient deposition of the H3K4me3 mark. We also reported in collaboration with Frank Holstege that H3K4 trimethylation loss on its own had little effect on steady-state mRNA expression levels and that the combined loss of H3K4me3 and H3K4me2 results in steady-state upregulation of a group of genes associated with Set1-mediated repression of 3’-end antisense transcription.

15 years ago, we demonstrated that inactivation of Set1 reduces the number of DSBs and impairs meiotic replication. This seminal paper was the first observation linking Set1 and H3K4 methylation to replication and to meiosis. In collaboration with Alain Nicolas and Valérie Borde, it was further shown that meiotic DSBs occur in regions showing higher H3K4me3 occupancy, although no higher transcript levels were detected near these DSB sites. We further reported that tethering of the PHD-containing protein, Spp1 to recombinationally cold regions was sufficient to induce DSB formation. Furthermore, we found that Spp1 physically interacted with Mer2, a key protein of the differentiated chromosomal axis required for DSB formation. Thus Spp1, by interacting with H3K4me3 and Mer2, promotes recruitment of potential meiotic DSB sites to the chromosomal axis. In collaboration with Lóránt Székvölgyi, we recently reported that spatial interactions of Spp1 and Mer2 occurred independently of Set1C. Our work led us to propose an enriched chromatin loop-axis model for the regulation of DSB formation that addresses how the meiotic DSB sites are mechanistically selected.


Cells respond to replication stress by signalling and repairing stalled replication forks. These mechanisms operate in the context of nascent chromatin and depend on the controlled resection of nascent DNA strands. However, how chromatin impacts on fork progression and stability remains poorly understood. We investigate how Set1C cooperate with chromatin remodellers to promote the remodelling of newly replicated chromatin to facilitate fork progression or restart.