2-AAF-induced tumor development in nucleotide excision repair-deficient mice is associated with a defect in global genome repair but not with transcription coupled repair.
The nucleotide excision repair (NER) pathway comprises two sub-pathways, transcription coupled repair (TCR) and global genome repair (GGR). To establish the importance of these separate sub-pathways in tumor suppression, we exposed mice deficient for either TCR (Csb), GGR (Xpc) or both (Xpa) to 300 ppm 2-acetylaminofluorene (in feed, ad libitum) in a unique comparative exposure experiment. We found that cancer proneness was directly linked to a defect in the GGR pathway of NER as both Xpa and Xpc mice developed significantly more liver tumors upon 2-AAF exposure than wild type or Csb mice. In contrast, a defect in TCR appeared to act tumor suppressive, leading to a lower hepatocellular tumor response in Xpa mice (tumor incidence of 25%) as compared to Xpc mice (53% tumor-bearing mice). The link between deficient GGR and tumor proneness was most pronounced in the liver, but this phenomenon was also found in the urinary bladder. As tumor induction by 2-AAF appeared almost exclusively dependent on a defect in GGR, we examined whether gene mutation induction in the non-transcribed lacZ locus could reliably predict tumor risk. Interestingly, however, short-term 2-AAF exposure induced lacZ mutant levels in Csb mice almost as high as those found in Xpa or Xpc mice. This indicates that lacZ mutant frequencies are not correlated with a specific DNA repair defect and eventual tumor outcome, at least not in the experimental design presented here.
Hoogervorst
Esther M
EM
Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
van Oostrom
Conny Th M
CT
Beems
Rudolf B
RB
van Benthem
Jan
J
van den Berg
Jolanda
J
van Kreijl
Coen F
CF
Vos
Joseph G
JG
de Vries
Annemieke
A
van Steeg
Harry
H
D015073:2-Acetylaminofluorene / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D016678:Genome; D007763:Lac Operon / Q000235:genetics; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*
D015073:2-Acetylaminofluorene