STRUCTURAL EFFECT OF INTRA-STRAND CISPLATIN-CROSS-LINK ON PALINDROMICDNA-SEQUENCES

Three self-complementary DNA oligonucleotides, each having a single Gp G site, have been reacted with the anticancer platinum compound cis-Pt (NH3)(2)Cl-2 (cisplatin). Their covalent intra-strand didentate adduct s have been purified and studied by NMR. In d(GACCATATGG*TC), the two GG* 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-GpG* crosslink in dsDNA, similar to that first seen r ecently in another duplex (Yang et al., Biochemistry (1995) 34, 12912- 12920). In d([c7A]CC[c7G][c7G]CCGG*T), the CG*G*T segment of the deca mer is essentially single-stranded with the G8 in the syn conformatio n. In d([c7G]CC[c7G]CGG*C), two possible structures, a full duplex an d a staggered partial duplex, were formed. Therefore, the structural c onsequence of the incorporation of the GG* lesion site into palindrom ic sequences is dependent on the location of the lesion sites in the s equence. The destabilizing effect of GG* in dsDNA may facilitate the formation of a hairpin structure as shown recently (Iwamoto et al., J. Amer Chem. Sec. (1994) 116, 6238-6244). Such alternative structural d istortions may be relevant in understanding the protein recognition of the lesions induced by cisplatin.