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Nucleic Acids Research Advance Access originally published online on July 28, 2009
Nucleic Acids Research 2009 37(17):5714-5724; doi:10.1093/nar/gkp617
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Nucleic Acids Research, 2009, Vol. 37, No. 17 5714-5724
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome Integrity, Repair and Replication

Transient dsDNA breaks during pre-replication complex assembly

Emmanouil Rampakakis and Maria Zannis-Hadjopoulos*

Goodman Cancer Center and Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3A 1A3

*To whom correspondence should be addressed. Tel: +1 514 398 3536; Fax: +1 514 398 6769; Email: maria.zannis{at}mcgill.ca

Received May 6, 2009. Revised July 6, 2009. Accepted July 8, 2009.

Initiation of DNA replication involves the ordered assembly of the multi-protein pre-replicative complex (pre-RC) during G1 phase. Previously, DNA topoisomerase II (topo II) was shown to associate with the DNA replication origin located in the lamin B2 gene locus in a cell-cycle-modulated manner. Here we report that activation of both the early-firing lamin B2 and the late-firing hOrs8 human replication origins involves DNA topo II-dependent, transient, site-specific dsDNA-break formation. Topo IIβ in complex with the DNA repair protein Ku associates in vivo and in vitro with the pre-RC region, introducing dsDNA breaks in a biphasic manner, during early and mid-G1 phase. Inhibition of topo II activity interferes with the pre-RC assembly resulting in prolonged G1 phase. The data mechanistically link DNA topo IIβ-dependent dsDNA breaks and the components of the DNA repair machinery with the initiation of DNA replication and suggest an important role for DNA topology in origin activation.


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