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 inherited defect in nucleotide excision repair (NER). While xeroderma pigmentosum (XP) patients have elevated skin cancer rates, Cockayne syndrome (CS) patients do not appear to have increased cancer susceptibility. To investigate whether differences in mutagenesis are the basis for the variability in cancer 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-benz[a]anthracene (DMBA) exposure in total NER-deficient Xpa mice, global genome repair (GGR)-deficient Xpc mice and transcription coupled repair (TCR)-deficient Csb mice. Surprisingly, while all intraperitoneally-treated Xpc(-/-) mice survived a dose of 40 mg/kg DMBA, a substantial fraction of the treated Xpa(-/-) and Csb(-/-) mice died a few days after treatment with a 20-fold lower dose. Functional TCR of DMBA adducts in Xpc(-/-) mice thus appears to alleviate DMBA toxicity. However, the mutagenic response in Xpc(-/-) mice 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 dermal fibroblasts were significantly enhanced in Xpa- and Csb-, but not in Xpc-deficient background compared to the frequency in normal fibroblasts. These results indicate that both damage-induced cytotoxicity as well as intra-chromosomal recombinational events were not correlated to differences in cancer susceptibility in human NER syndrome patients.
Wijnhoven
S W
SW
Department of Radiation Genetics and Chemical Mutagenesis-MGC, Leiden University Medical Center, The Netherlands.
Kool
H J
HJ
Mullenders
L H
LH
Slater
R
R
van Zeeland
A A
AA
Vrieling
H
H
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D012854:Sister Chromatid Exchange; D012867:Skin / Q000166:cytology / Q000187:drug effects; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D009153:Mutagens; D000075223:Poly-ADP-Ribose Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C501002:Xpc protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D004265:DNA Helicases; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes