DMBA-induced toxic and mutagenic responses vary dramatically between NER-deficient Xpa, Xpc and Csb mice

Heterogeneity in cancer susceptibility exists between patients with an inhe rited defect in nucleotide excision repair (NER), While xeroderma pigmentos um (XP) patients have elevated skin cancer rates, Cockayne syndrome (CS) pa tients do not appear to have increased cancer susceptibility. To investigat e whether differences in mutagenesis are the basis for the variability in c ancer proneness, we studied mutagenesis at the X-chromosomal Hprt gene and the autosomal Aprt gene in splenic T-lymphocytes after 7,12-dimethyl-1,2-be nz[a]anthracene (DMBA) exposure in total NER-deficient Xpa mice, global gen ome repair (GGR)deficient Xpc mice and transcription coupled repair (TCR)-d eficient Csb mice. Surprisingly, while all intraperitoneally-treated Xpc(-/ -) mice survived a dose of 40 mg/kg DMBA, a substantial fraction of the tre ated Xpa(-/-) and Csb(-/-) mice died a few days after treatment with a 20-f old lower dose. Functional TCR of DMBA adducts in Xpc(-/-) mice thus appear s to alleviate DMBA toxicity. However, the mutagenic response in Xpc(-/-) m ice was +/- 2-fold enhanced at both the Hprt and the Aprt gene compared to heterozygous controls, indicating that GGR at least partially removes DMBA adducts from the genome overall. DMBA-induced SCE frequencies in mouse derm al fibroblasts were significantly enhanced in Xpa- and Csb-, but not in Xpc -deficient background compared to the frequency in normal fibroblasts, Thes e results indicate that both damage-induced cytotoxicity as well as intrach romosomal recombinational events were not correlated to differences in canc er susceptibility in human NER syndrome patients.