Thermal stability of DNA with interstrand crosslinks

Abstract

Although many anticancer drugs exert their biological activity by forming DNA interstrand crosslinks (ICLs), the thermodynamics of biologically relevant long crosslinked DNAs has not been intensively studied in contrast to short duplexes. Here, we carry out computer modeling of the shift of melting temperature of long DNAs caused by ICLs taking into account crosslinking effect in itself and concomitant local alterations in the free energy (δG) of the helix-coil transition at sites of ICLs. Depending on δG, DNA interstrand crosslinks at per nucleotide concentration r = 0.05 can change the melting temperature by value from -17 to +47°C, and the influence weakly depends on DNA sequence and GC content. A change in melting temperature caused by introduction of interstrand crosslinking in modified DNA at sites of modifications also depends on δG and varies from 0 to +12°C. Comparison with experiment for the three platinum crosslinking compounds demonstrates utility of the theoretical method for understanding how crosslinking compounds can influence the melting behavior. On the basis of the method, interdependence of local distortions and crosslinking in itself was studied for thermal effect of ICLs. A method for evaluating the nature of the structural alteration that produces a change in thermal stability for short crosslinked DNA is also proposed. The methods can be used for comparative thermodynamic characterization of various DNA crosslinking agents.

Platinum nanoparticles induce damage to DNA and inhibit DNA replication

“…Hundreds of Pt(II) and Pt(IV) complexes have been synthesized since the discovery the antibacterial effects of platinum in 1965 [42–44]. The effect of the platinum complexes (cisplatin, carboplatin and oxaliplatin) is most probably based on their covalent binding with DNA bases [45, 46] forming intra- and interstrand crosslinks, DNA—protein crosslinks, and monoadducts with DNA [47]. DNA secondary structures can block transcription and replication with subsequent apoptosis [48].…”

“…This finding may be caused by the fact that the alkaline comet assay is more sensitive to dsDNA breakage than to ssDNA breakage. In case of CisPt, ssDNA breakage [69], and covalent binding to DNA and interstrand crosslink [45] were observed as a result of a direct interaction with the DNA. The dsDNA breakages were caused rather by the PtNPs-induced Pt 2+ ions formed during the incubation of the PtNPs with DNA [23].…”

Temporal behavior of DNA thermal stability in the presence of platinum compounds. Role of monofunctional and bifunctional adducts

“…From the data on melting of oligonucleotide duplexes [39], one can obtain that local distortions formed by cisplatin and transplatin interstrand crosslinks give rise to the following change in the free energy (kcal/mol duplexes) of the helix-coil transition: δG=-18+0.037⋅T K and δG =-2-0.015⋅T K, respectively. Our calculations [49,66,78] demonstrate that, in long DNA, such interstrand crosslinks cause a very small change in thermal stability (less than 0.3°C). These estimations are valid for alkaline medium where a stabilizing electrostatic effect is eliminated that makes the situation similar to the case of oligonucleotide duplexes.…”

“…Besides a local change in DNA structure and thermal stability that is generated by all types of chemical modifications, interstrand crosslinks increase the thermal stability of short DNAs prohibiting strand dissociation [39,40,62,63]. Additional stabilization of long DNAs is caused by formation of additional loops in melted regions [73][74][75][76][77][78]. The fraction of interstrand crosslinks accounts for 6% and 12% for cisplatin and transplatin, respectively [10][11][12].…”

Neo-epitopes on crotonaldehyde modified DNA preferably recognize circulating autoantibodies in cancer patients

“…However, alteration occurred in the shape and position of DSC curve after crotonaldehyde modification due to reduction in DSC curve along with gradual disappearance of four narrow peaks that are involved in fine structure formation. Besides, there was an increase in the melting temperature of native and modified DNA from 84 to 90.2°C attributable to crosslinking in DNA [33]. Earlier studies have shown that transplatin enhances the melting temperature that results from interstrand crosslink formation and/or decrease in thermal destabilization due to structural changes [34].…”