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Organization of DNA Replication Origin Firing in Xenopus Egg Extracts: The Role of Intra-S Checkpoint.
Genes (Basel), 12(8).
During cell division, the duplication of the genome starts at multiple positionscalled replication origins. Origin firing requires the interaction of rate-limitingfactors with potential origins during the S(ynthesis)-phase of the cell cycle.Origins fire as synchronous clusters which is proposed to be regulated by theintra-S checkpoint. By modelling the unchallenged, the checkpoint-inhibited and thecheckpoint protein Chk1 over-expressed replication pattern of single DNA moleculesfrom Xenopus sperm chromatin replicated in egg extracts, we demonstrate that thequantitative modelling of data requires: (1) a segmentation of the genome intoregions of low and high probability of origin firing; (2) that regions with highprobability of origin firing escape intra-S checkpoint regulation and (3) thevariability of the rate of DNA synthesis close to replication forks is a necessaryingredient that should be taken in to account in order to describe the dynamic ofreplication origin firing. This model implies that the observed origin clusteringemerges from the apparent synchrony of origin firing in regions with highprobability of origin firing and challenge the assumption that the intra-Scheckpoint is the main regulator of origin clustering.
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