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A more recent version of this article appeared on December 1, 2006
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Submitted on April 11, 2006
Revised on September 8, 2006
Accepted on September 20, 2006
*Unité de Stabilité des Génomes, Institut Pasteur, 75724, Paris, France; Genoscope, Centre National de Séquençage, 91000, Evry, France; Upper Austrian Research, Zentrum für Biommedizinische Nanotechnologie, 4020, Linz, Austria
Monitoring Editor: A. Gregory Matera
Mammalian DNA replication origins localize to sites that range from base pairs’s to tens of kb’s. A regular distribution of initiations in individual cell cycles suggests that only a limited number of these numerous potential start sites are converted into activated origins. Origin interference can silence redundant origins; however, it is currently unknown whether interference participates in spacing functional human initiation events. By using a novel hybridization strategy, Genomic Morse Code, on single combed DNA molecules from primary keratinocytes, we report the initiation sites present on 1.5 Mb of human chromosome 14q11.2. We confirm that initiation zones are widespread in human cells, map to intergenic regions, and contain sequence motifs found at other mammalian initiation zones. Origins used per cell cycle are less abundant than the potential sites of initiation and their limited use increases the spacing between initiation events. Between-zone interference decreases in proportion to the distance from the active origin, while within-zone interference is 100% efficient. These results identify a hierarchical organization of origin activity in human cells. Functional origins govern the probability that nearby origins will fire in the context of multiple potential start sites of DNA replication and this is mediated by origin interference.
Present address: Harvard Medical School, Boston, MA 02115.
Address correspondence to:
Aaron Bensimon (abensim{at}pasteur.fr)
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