MAMMALIAN-CELLS SHARE A COMMON PATHWAY FOR THE RELIEF OF DNA-REPLICATION ARREST BY O6-ALKYL GUANINE, INCORPORATED 6-THIOGUANINE AND UV PHOTOPRODUCTS

We previously reported the cloning of a mammalian gene that restores UV resistance to a postreplication recovery defective and mex- Indian muntjac mutant cell line, SVM, by improving daughter-strand DNA replication on a UV-damaged template. The improved replication was, however, found to bc error-prone, as judged by a hypermutable phenotype (Bouffler et al. (1990) Somatic Cell Mol. Genet., 16, 507-516). We now report that this gene also increases the resistance of SVM to the cytotoxic effects of methyl- and ethyl-nitrosourea, though not to dimethyl sulphate, by a similar postreplication recovery process. The gene does not increase the activity of O6-alkylguanine-DNA-alkyltransferase in the cell. We conclude that at least one mechanism of postreplication recovery in mammalian cells allows UV photoproducts and O6-alkylguanine lesions to be tolerated by the replication complex. The fact that the gene also confers resistance to 6-thioguanine suggests that, once incorporated, this base analogue can disrupt normal DNA replication and that a single mechanism can allow replication to proceed beyond diverse DNA lesions.