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Vol. 18, Issue 8, 3059-3067, August 2007

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Replication Fork Velocities at Adjacent Replication Origins Are Coordinately Modified during DNA Replication in Human Cells

Chiara Conti^*,,, Barbara Saccà^*,,, John Herrick^*, Claude Lalou^||, Yves Pommier^¶, and Aaron Bensimon^*,#

*Department of Genome Stability, Pasteur Institute, Paris F-75724, France; ^||Institut National de la Santé et de la Recherche Médicale U532, Hôpital Saint-Louis, Paris 75010, France; and ^¶Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20817

Submitted August 8, 2006; Revised May 1, 2007; Accepted May 16, 2007
Monitoring Editor: A. Gregory Matera

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. 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. Mechanisms coordinating origin distribution with fork progression are still poorly elucidated, because of technical difficulties of visualizing the process. 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. 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. We also found that forks that emanated from closely spaced origins tended to move slower than those associated with long replicons. Taken together, our results indicate a functional role for origin clustering in the dynamic regulation of genome duplication.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Present addresses: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20817;

Department of Chemistry, University of Dortmund, D-44227 Dortmund, Germany;

^# Genomic Vision, 27 Rue du Faubourg Saint-Jacques, Pavillon Gustave Roussy, Paris 75014, France.

Address correspondence to: Aaron Bensimon (aaron.bensimon{at}genomicvision.com).

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