Structural effect of intra-strand cisplatin-crosslink on palindromic DNA sequences.

Abstract

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 intra-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.