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Marie-Noëlle Prioleau — Control of the spatio-temporal program of DNA replication in vertebrates
Speaker :
Marie-Noëlle Prioleau, Institut Jacques-Monod, Paris
When :
Wednesday 12 January at 11am
Where :
C023 (RDC LR6 côté Centre Blaise Pascal)
Title :
Control of the spatio-temporal program of DNA replication in vertebrates
Abstract :
DNA replication must be tightly regulated to ensure genome stability. The mechanisms regulating the coordinate activation of tens of thousands of replication origins in multicellular organisms remain poorly explored. The nuclear genomes of vertebrates show a highly organized program of DNA replication where GC-rich isochores are replicated early in S phase, while AT-rich isochores are late replicating. GC-rich regions are gene dense and are enriched for active transcription, suggesting a connection between gene regulation and the molecular mechanisms responsible for a well ordered firing of DNA replication origins. One of our goal was to identify a minimal combination of cis-regulatory elements that have a capacity to form an autonomous replicon activated in the first half of S-phase. Insulator elements can organize independent domains of gene transcription and are suitable candidates for being key regulators of replication timing. We have tested the impact of inserting a strong replication origin flanked by the β-globin HS4 insulator, on the replication timing of naturally late replicating regions. We find that the HS4 insulator has the capacity to impose early activation on a replication origin resulting in a shift in replication timing of the target locus from the second half of S-phase to the first half. Moreover, we find that the binding site for USF transcription factors is the key element inside HS4 responsible for replication timing control. Taken together, our data identify a combination of cis-elements that might constitute the basic unit of multi-replicon megabase-sized early domains of DNA replication therefore providing important information about the elements and mechanisms that shape vertebrate genomes. We have also developed high-resolution maps of replication origins in human in order to define general rules governing origin positioning. We have found that most origins overlap with transcriptional regulatory elements suggesting again a complex interplay between DNA replication and transcription. These aspects will also be discussed.
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