Ring-opened alkylated guanine is not repaired in Z-DNA

Abstract

Since the discovery of Z-DNA by X-ray analysis of the alternated hexanucleotide d(C-G)3 crystals, numerous studies have shown that fragments of natural DNAs can adopt the Z conformation, topological constraints being a major factor stabilizing this conformation. Immunochemical assays using antibodies to Z-DNA provide strong evidence for the presence of Z fragments in chromosomes. The biological role of Z-DNA is not yet known, but it might be involved in gene regulation. Proteins which bind specifically to Z-DNA have been isolated and interactions between Z-DNA and several cellular proteins have been studied. The ability of DNA repair enzymes to maintain the genome's integrity is of major importance to the cell. On alkylation of DNA by chemical carcinogens such as dimethyl sulphate, methyl methanesulphonate, methylnitrosourea or methylnitrosoguanidine, the main target is the N7 of the guanosine residue, yielding 7-methylguanine (mG). In alkaline conditions, the imidazole ring of mG opens up, yielding the ring-opened form 2,6-diamino-4-oxo-5-methylformamidopyrimidine (rom7G); this lesion is a block to DNA replication. It occurs in vivo and is enzymatically removed by the DNA glycosylase. Here we report that the lesion is not excised when present in DNA in the left-handed Z conformation.