4/7/2023 0 Comments Replication fork![]() Origins are dynamically regulated by a number of cis-acting, metabolic and epigenetic factors depending on the transcriptional and developmental programs ( Maric et al., 1999 Sasaki et al., 1999 Aladjem and Fanning, 2004 Danis et al., 2004). In metazoans, origins of replication are generally not encoded by specific sequences ( DePamphilis, 1999 Todorovic et al., 1999 Gilbert, 2001 Mechali, 2001). In spite of its importance in the transmission of genetic information, the regulation of origin distribution and fork progression and the coordination of these two processes still remain to be fully elucidated in human cells. The efficient duplication of the eukaryotic genome depends on the orderly activation of those origins, estimated to be several tens of thousands, and on the proper progression of their forks. In metazoan cells, DNA replication initiates at multiple sites, called origins of replication, from which two forks emanate and progress bidirectionally. The complete and correct duplication of the genome once and only once per cell cycle is one of the most challenging cellular tasks. Taken together, our results indicate a functional role for origin clustering in the dynamic regulation of genome duplication. We also found that forks that emanated from closely spaced origins tended to move slower than those associated with long replicons. Our results show that replication forks moving from one origin, as well as from neighboring origins, tend to exhibit the same velocity, although the plasticity of the replication program allows for their adaptation to variable interorigin distances. Taking advantage of a single molecule approach, we delineated and compared the DNA replication kinetics at the genome level in human normal primary and malignant cells. ![]() Mechanisms coordinating origin distribution with fork progression are still poorly elucidated, because of technical difficulties of visualizing the process. The coordinated activation of origins is insufficient on its own to account for a timely completion of genome duplication when interorigin distances vary significantly and fork velocities are constant. The spatial organization of replicons into clusters is believed to be of critical importance for genome duplication in higher eukaryotes, but its functional organization still remains to be fully clarified. ![]()
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