Institut de Biologie de l'École Normale Supérieure ENS . CNRS UMR8197 . Inserm U1024 Directeur : Pierre Paoletti

Research topic

The "Maintenance of genome integrity" is the main theme of my research work. I currently study Common Fragile Sites (CFS), which are loci hypersensitive to replication stress and are hotspots for chromosomal rearrangements in cancers. CFSs are epigenetically defined, are cell-type specific and coincide with large genes, but the role of transcription in their fragility is debated. To address this issue, I have manipulated the transcription of selected endogenous large genes and analysed its impact on their replication dynamics and fragility. Remarkably, I found that fragility is set by low transcription yet is alleviated by high transcriptional levels. To explain these results, I have shown that transcription quantitatively shapes the replication program of large genes, setting both their initiation profile and their replication timing as well as regulating internal fork velocity. Noticeably, high transcription levels advance the replication time of large genes from late to mid S-phase, which most likely gives cells more time to complete replication before mitotic entry. Transcription can therefore contribute to maintaining the integrity of some difficult-to-replicate loci, challenging the dominant view that it is exclusively a threat to genome stability. I am currently involved in the development of new genome-wide replication analysis techniques to better understand the links between transcription and replication.