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Vol. 17, Issue 12, 5337-5345, December 2006

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DNA Replication Origin Interference Increases the Spacing between Initiation Events in Human Cells

Ronald Lebofsky^*,, Roland Heilig, Max Sonnleitner, Jean Weissenbach, and Aaron Bensimon^*

*Unité de Stabilité des Génomes, Institut Pasteur, 75724, Paris, France; Genoscope, Centre National de Séquençage, 91000, Evry, France; and Upper Austrian Research, Zentrum für Biommedizinische Nanotechnologie, 4020, Linz, Austria

Submitted April 11, 2006; Revised September 8, 2006; Accepted September 20, 2006
Monitoring Editor: A. Gregory Matera

Mammalian DNA replication origins localize to sites that range from base pairs to tens of kilobases. 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, whereas 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.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-04-0298) on September 27, 2006.

Present address: Harvard Medical School, Boston, MA 02115.

Address correspondence to: Aaron Bensimon (abensim{at}pasteur.fr)

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