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Published online 20 May 2004

Nucleic Acids Research, 2004, Vol. 32, No. 9 2795-2801
© 2004 Oxford University Press

Sequence context effect on the structure of nitrous acid induced DNA interstrand cross-links

N. B. Fredrik Edfeldt*, Eric A. Harwood, Snorri Th. Sigurdsson, Paul B. Hopkins and Brian R. Reid

Department of Chemistry, University of Washington, Seattle, WA 98195, USA

*To whom correspondence should be addressed at present address: AstraZeneca Structural Chemistry Laboratory, AstraZeneca R&D Mölndal, 431 83, Mölndal, Sweden. Tel: +46 31 776 1604; Fax: +46 31 776 3792; Email: fredrik.edfeldt{at}astrazeneca.com
Present address:
Eric A. Harwood, Chiron Corporation, 201 Elliott Avenue West, Suite 150, Seattle, WA 98119, USA

Received January 7, 2004; Revised and Accepted April 22, 2004

In the preceding paper in this journal, we described the solution structure of the nitrous acid cross-linked dodecamer duplex [d(GCATCCGGATGC)]2 (the cross-linked guanines are underlined). The structure revealed that the cross-linked guanines form a nearly planar covalently linked ‘G:G base pair’, with the complementary partner cytidines flipped out of the helix. Here we explore the flanking sequence context effect on the structure of nitrous acid cross-links in [d(CG)]2 and the factors allowing the extrahelical cytidines to adopt such fixed positions in the minor groove. We have used NMR spectroscopy to determine the solution structure of a second cross-linked dodecamer duplex, [d(CGCTACGTAGCG)]2, which shows that the identity of the flanking base pairs significantly alters the stacking patterns and phosphate backbone conformations. The cross-linked guanines are now stacked well on adenines preceding the extrahelical cytidines, illustrating the importance of purine– purine base stacking. Observation of an imino proton resonance at 15.6 p.p.m. provides evidence for hydrogen bonding between the two cross-linked guanines. Preliminary structural studies on the cross-linked duplex [d(CGCGACGTCGCG)]2 show that the extrahelical cytidines are very mobile in this sequence context. We suggest that favorable van der Waals interactions between the cytidine and the adenine 2 bp away from the cross-link localize the cytidines in the previous cross-linked structures.


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N. B. F. Edfeldt, E. A. Harwood, S. Th. Sigurdsson, P. B. Hopkins, and B. R. Reid
Solution structure of a nitrous acid induced DNA interstrand cross-link
Nucleic Acids Res., May 20, 2004; 32(9): 2785 - 2794.
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