The role of nucleotide excision repair and loss of p53 in mutagenesis and carcinogenesis.

Xpa mice, which have a completely defective nucleotide excision repair (NER) pathway, have a cancer predisposition when exposed to several carcinogens. NER is one of the major DNA repair pathways in the mammalian cell, and is involved in the removal of a wide variety of DNA lesions, such as those induced by UV light, bulky adducts and DNA crosslinks. To study the role of NER in both mutagenesis and carcinogenesis, NER-defective Xpa mice were crossed with transgenic lacZ/pUR288 mutation-indicator mice. Furthermore, the relationship between the tumor suppressor gene p53, NER, induction of mutations and tumor development was studied in Xpa/p53+/-/lacZ triple transgenic mice. Using the genotoxic carcinogens benzo[a]pyrene (B[a]P) and 2-acetylaminofluorene (2-AAF), it is shown that mutations in the inactive (non-transcribed) lacZ reporter gene reliably predict cancer risk. In tissues at risk for the development of tumors, increased mutant frequencies could be found at much earlier stages. A heterozygous loss of p53 appears to act synergistically to a NER defect, both in mutation- as well as tumor-induction. Surprisingly, however, the effect of a heterozygous loss of p53 appeared to be tissue-restricted, being apparent in the bladder but absent in liver and spleen.