SUNY at Albany
June 19-23, 2001
Interstrand Cross-Linking Caused by Local Stabilization of the Double Helix
DNA interstrand cross-links are usually formed due to bidentate covalent or strong coordination binding of a cross-linking agent to nucleotides of different strands. However interstrand linkage can be also caused by strong stabilization of one or several adjacent base pairs in the double helix. As a result, these stabilized regions are saved their helical structure at high temperature after almost full melting of ordinary AT and GC base pairs. Like covalent interstrand cross-links, this local stabilization makes DNA melting fully reversible and independent of strand concentration. Such an effect can be caused by all the types of chemical modifications (interstrand cross-links, intrastrand cross-links or monofunctional adducts) if they give rise to strong enough stabilization of the double helix. Criterion of interstrand cross-linking caused by stabilization was developed and used for determination of a minimum increase in stability that causes interstrand cross-linking. It is shown that increasing by 24 kcal in the enthalpy (or free energy) of the helix-coil transition of a single base pair in the double helix is enough for cross-linking effect independently of the DNA length. Some metal-based antitumor compounds give rise to such stabilizing cross-linking. If this stabilization is distributed along several neighboring base pairs then required minimum increase per stabilized base pair is lower (1bp - 24kcal; 5bp - 5.2kcal; 20bp - 1.4; 50bp - 0.67kcal). It means that relatively weak non-covalent binding of histones or protamines that cover long regions of DNA (more than 20-40bp) can cause such a cross-linking effect if salt concentration of DNA solution is low. This work was supported by Fund of Fundamental Investigations of the Republic of Belarus, Grant No X99R-099 and by CRDF Foundation (USA) (Award # AB2-2006).
Alexander S. Fridman, Samvel G. Haroutiunian and Dmitri Y. Lando
Institute of Bioorganic Chemistry, Belarus National Academy of Sciences, Kuprevich St. 5/2, 220141 Minsk, Belarus;