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 be 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 3 diverse DNA lesions.
Godfrey
D B
DB
Department of Zoology, Cambridge University, UK.
Bouffler
S D
SD
Musk
S R
SR
Raman
M J
MJ
Johnson
R T
RT
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D003670:Deer; D005038:Ethylnitrosourea / Q000633:toxicity; D005796:Genes; D008770:Methylnitrosourea / Q000633:toxicity; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology; D012854:Sister Chromatid Exchange; D013866:Thioguanine / Q000494:pharmacology; D014162:Transfection
D000477:Alkylating Agents; D009588:Nitrogen Mustard Compounds; D008770:Methylnitrosourea; C040369:mitozolomide; D008780:Methyltransferases; D013866:Thioguanine; D005038:Ethylnitrosourea