title: Tissue specific mutagenic and carcinogenic responses in NER defective mouse models.
abstract: Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) are - except for the skin - not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features.
authors.affiliation: National Institute of Public Health and the Environment (RIVM), Laboratory of Toxicology, Pathology and Genetics, PO Box 1, 3720 BA, Bilthoven, The Netherlands.
authors.forename: Susan W P
authors.initials: SW
authors.lastname: Wijnhoven
authors.forename: Esther M
authors.initials: EM
authors.lastname: Hoogervorst
authors.forename: Harm
authors.initials: H
authors.lastname: de Waard
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D009928:Organ Specificity; D010641:Phenotype; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism
chemical_list: D002273:Carcinogens; D009153:Mutagens