Structural effect of intra-strand cisplatin-crosslink on palindromic dna sequences

Three self-complementary DNA oligonucleotides, each having a single GpG site, have been reacted with the anticancer platinum compound cis–Pt(NH₃)₂Cl₂ (cisplatin). Their covalent intra-strand didentate adducts have been purified and studied by NMR. In d(GAC- CATATG*G*TC), the two G*G* sites (G*G* denoting the cisplatin crosslinked lesion site) are separated by four base pairs and capped by two base pairs at the ends of the helix and the dodecamer forms a doubly-kinked duplex structure. Multi-stranded aggregate of the dodecamer was formed over time in the presence of chloride. This is due to the meta-stable property of the infra-strand Pt-G*pG* crosslink in dsDNA, similar to that first seen recently in another duplex (Yang et al., Biochemistry (1995) 34, 12912–12920). In d([c⁷A]CC[c⁷G] [c⁷G]CCG*G*T), the CG*G*T segment of the decamer is essentially single-stranded with the G*8 in the syn conformation. In d([c⁷G]CC[c⁷G]CG*G*C), two possible structures, a full duplex and a staggered partial duplex, were formed. Therefore, the structural consequence of the incorporation of the G*G* lesion site into palindromic sequences is dependent on the location of the lesion sites in the sequence. The destabilizing effect of G*G* in dsDNA may facilitate the formation of a hairpin structure as shown recently (Iwamoto et al., J. Amer. Chem. Soc. (1994) 116, 6238–6244). Such alternative structural distortions may be relevant in understanding the protein recognition of the lesions induced by cisplatin.