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Nucleic Acids Research Advance Access published online on November 11, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp929
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© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/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

Origin-dependent initiation of DNA replication within telomeric sequences

Isabel Kurth and Jean Gautier*

Institute for Cancer Genetics, Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA

*To whom correspondence should be addressed. Tel: +1 212 851 4564; Fax: +1 212 851 5284; Email: jg130{at}columbia.edu

Received March 15, 2009. Revised October 7, 2009. Accepted October 8, 2009.

Replication of telomeres requires the action of telomerase, the semi-conservative replication machinery and the stabilization of the replication fork during passage through telomeric DNA. Whether vertebrate telomeres support initiation of replication has not been experimentally addressed. Using Xenopus cell free extracts we established a system to study replication initiation within linear telomeric DNA substrates. We show binding of TRF2 to telomeric DNA, indicating that exogenous DNA exclusively composed of telomeric repeats is recognized by shelterin components. Interaction with telomere binding proteins is not sufficient to prevent a DNA damage response. Notably, we observe regulated assembly of the pre-replicative complex proteins ORC2, MCM6 and Cdc6 to telomeric DNA. Most importantly, we detect origin-dependent replication of telomeric substrates under conditions that inhibit checkpoint activation. These results indicate that pre-replicative complexes assemble within telomeric DNA and can be converted into functional origins.

Present address: Isabel Kurth, Rockefeller University, 1230 York Avenue, Box 228, New York, NY, 10065, USA.


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