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 in duced by UV light, bulky adducts and DNA crosslinks. To study the role of N ER in both mutagenesis and carcinogenesis, NER-defective Xpa mice were cros sed with transgenic lacZ/pUR288 mutation-indicator mice. Furthermore, the r elationship between the tumor suppressor gene p53, NER, induction of mutati ons and tumor development was studied in Xpa/p53 +/- /lacZ triple transgeni c mice. Using the genotoxic carcinogens benzo[a]pyrene (B[a]P) and 2-acetyl aminofluorene (2-AAF), it is shown that mutations in the inactive (non-tran scribed) lacZ reporter gene reliably predict cancer risk. In tissues at ris k for the development of tumors, increased mutant frequencies could be foun d at much earlier stages. A heterozygous loss of p53 appears to act synergi stically to a NER defect, both in mutation- as well as tumor-induction. Sur prisingly, however, the effect of a heterozygous loss of p53 appeared to be tissue-restricted, being apparent in the bladder but absent in liver and s pleen. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.