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Nucleic Acids Research Advance Access originally published online on January 16, 2009
Nucleic Acids Research 2009 37(5):1555-1565; doi:10.1093/nar/gkn1077
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Nucleic Acids Research, 2009, Vol. 37, No. 5 1555-1565
© 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.

Chemistry and Synthetic Biology

Furan-modified oligonucleotides for fast, high-yielding and site-selective DNA inter-strand cross-linking with non-modified complements{dagger}

Kristof Stevens and Annemieke Madder*

Laboratory for Organic and Biomimetic Chemistry, Department of Organic Chemistry, Ghent University, Krijgslaan 281, S4, 9000 Gent, Belgium

*To whom correspondence should be addressed. Tel: +32 9 264 44 72; Fax: +32 9 264 49 98; Email: annemieke.madder{at}ugent.be

Received November 25, 2008. Revised December 21, 2008. Accepted December 22, 2008.

Among the various types of DNA damage, inter-strand cross-links (ICL) represent one of the most cytotoxic lesions. Processes such as transcription and replication can be fully blocked by ICLs, as shown by the mechanism of action of some anticancer drugs. However, repair of ICLs can be a possible cause of resistance. To study the mechanisms of cross-link repair stable, site-specifically cross-linked duplexes are needed. We here report on the synthesis of site-specifically cross-linked DNA using an acyclic furan containing nucleoside. Selective in situ oxidation of the incorporated furan moiety generates a highly reactive oxo-enal that instantly reacts with the complementary base in a non-modified strand, yielding one specific stable cross-linked duplex species. Varying sequence context showed that a strong selectivity for cross-linking to either complementary A or complementary C is operating, without formation of cross-links to neighboring or distant bases. Reaction times are very short and high isolated yields are obtained using only one equivalent of modified strand. The formed covalent link is stable and the isolated cross-linked duplexes can be stored for several months without degradation. Structural characterization of the obtained ICL was possible by comparison to the natural mutagenic adducts of cis-2-butene-1,4-dial, a metabolite of furan primarily responsible for furan carcinogenicity.

{dagger}Dedicated to Prof. Pierre J. De Clercq at the occasion of his 60th birthday.


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