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Nucleic Acids Research Advance Access originally published online on August 31, 2006
Nucleic Acids Research 2006 34(16):4458-4466; doi:10.1093/nar/gkl587
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Nucleic Acids Research, 2006, Vol. 34, No. 16 4458-4466
© 2006 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.

Chemistry

A modified thymine for the synthesis of site-specific thymine-guanine DNA interstrand crosslinks

Jawad Alzeer1 and Orlando D. Schärer1,2,*

1 Institute of Molecular Cancer Research, University of Zurich Winterthurerstrasse 190, 8057 Zurich, Switzerland 2 Department of Pharmacological Sciences, Chemistry Graduate Building 619, Stony Brook University Stony Brook, NY11794-3400

*To whom correspondence should be addressed. Tel: +1 631 632-77545; Fax: +1 631 632-7546; Email: orlando{at}pharm.stonybrook.edu

Received June 22, 2006. Revised July 26, 2006. Accepted July 28, 2006.

DNA interstrand crosslinks (ICLs) are highly cytotoxic lesions formed by a variety of important anti-tumor agents. Despite the clinical importance of ICLs, the mechanisms by which these lesions are repaired in mammalian cells have so far remained elusive. One of the obstacles in the study of ICL repair has been the limited availability of suitable methods for the synthesis of defined site-specific ICLs. We report here the synthesis of a site-specific ICL containing an ethylene-bridged G-T base pair based on the incorporation of a crosslink precursor containing a selectively reactive group on one strand using solid-phase synthesis. 3-(2-chloroethyl)thymidine was incorporated into oligonucleotides and underwent ICL formation upon annealing to a complementary strand by reacting with the base opposite to the modified T residue. A strong preference for ICL formation with a G residue opposite the reactive T was observed. Detailed characterization of the reaction product revealed that the alkylation reaction occurred with the O-6 group of G and a mechanism accounting for this preference is proposed. These G-T crosslinks introduced here will be useful for studies of ICL repair.


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