Flanking Bases Influence the Nature of DNA Distortion by Platinum 1,2-Intrastrand (GG) Cross-Links

Abstract

The differences in efficacy and molecular mechanisms of platinum anti-cancer drugs cisplatin (CP) and oxaliplatin (OX) are thought to be partially due to the differences in the DNA conformations of the CP and OX adducts that form on adjacent guanines on DNA, which in turn influence the binding of damage-recognition proteins that control downstream effects of the adducts. Here we report a comprehensive comparison of the structural distortion of DNA caused by CP and OX adducts in the TGGT sequence context using nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations. When compared to our previous studies in other sequence contexts, these structural studies help us understand the effect of the sequence context on the conformation of Pt-GG DNA adducts. We find that both the sequence context and the type of Pt-GG DNA adduct (CP vs. OX) play an important role in the conformation and the conformational dynamics of Pt-DNA adducts, possibly explaining their influence on the ability of many damage-recognition proteins to bind to Pt-DNA adducts.

Comprehensive Comparative Analysis of the Morphological Changes in a 12-mer DNA Oligonucleotide upon Platination by Cisplatin, Oxaliplatin and BNP3029 (a Substituted Cyano ligand-based Platinum analogue) using Molecular Dynamics Simulation Studies

“…The current MD studies on platinated-DNA for cisplatin and oxaliplatin did not indicate significant hydrogen-bond patterns on the 5'-side of the platinum adduct (similar to the earlier results presented by Howell [19] and Chaney [21]). However, as shown in Figure 2S, we identified two different hydrogen-bonding patterns on the 3'-side of the platinum-DNA with cisplatin and oxaliplatin.…”

“…In a recent study, Chaney et al reported combined NMR and MD data for cisplatin-DNA and oxaliplatin-DNA (using the same sequence as used in this study) [21]. From the MD studies, no hydrogen-bond contacts were identified between platinum ligands and the 5'-DNA bases; whereas hydrogen-bond contacts between platinum ligands and the 3'-DNA bases were identified.…”

“…Platinum-DNA oligonucleotide adducts have been studied using crystallography [14][15][16], NMR [17,18], and computational approaches [19][20][21]. Crystallographic studies have previously been carried out on 12-mer DNA oligonucleotide adducts of cisplatin, oxaliplatin and JM118 (JM118 is the active metabolite of Satraplatin) by Lippard and coworkers [14][15][16].…”

DNA Polymerase ζ Is a Major Determinant of Resistance to Platinum-Based Chemotherapeutic Agents

“…Monoubiquitination of PCNA on Lys164 recruits TLS polymerases through a combination of protein-protein interacting motifs that include PCNA-interacting peptide and ubiquitin-binding domains. TLS polymerases possess accommodating active sites and are capable of replicating DNA containing bulky DNA lesions, even when the DNA template is distorted by adducts such as those created by cisplatin (Alt et al, 2007;Waters et al, 2009;Washington et al, 2010;Bhattacharyya et al, 2011).…”

Theoretical Study of the Structural and Energetics Properties of the Interaction Sides of Guanine and Adenine in Gg and Aa Trans Base Pairs

“…This is particularly interesting since it is observed 70% of GG sites and 20% of GA sites 3 in the DNA cancer cells. RMN studies and molecular dynamic simulation suggest that the Pt-GG DNA adduct modifies the structural properties of mutated DNA allowing the incorporation of the mismatch repair protein 16 . In Cu(II)-nucleobases interactions 17 , Adenine uses N3 atom to coordinate the divalent metal ion while Guanine uses N7 atom, evidencing the capability of the latter one to form metal-Guanine clusters in a similar configuration as the Guanine quartets observed in DNA 8,[18][19] , where interactions WC/H with cis glycosidic bond characterize the formation of hydrogen bonds amongst the purines, involving 4 molecules of Guanine.…”