title: The role of XPC: implications in cancer and oxidative DNA damage.
abstract: The accumulation of DNA damage is a slow but hazardous phenomenon that may lead to cell death, accelerated aging features and cancer. One of the most versatile and important defense mechanisms against the accumulation of DNA damage is nucleotide excision repair (NER), in which the Xeroderma pigmentosum group C (XPC) protein plays a prominent role. NER can be divided into global genome repair (GG-NER) and transcription coupled repair (TC-NER). XPC is a key factor in GG-NER where it functions in DNA damage recognition and after which the repair machinery is recruited to eliminate the DNA damage. Defective XPC functioning has been shown to result in a cancer prone phenotype, in human as well as in mice. Mutation accumulation in XPC deficient mice is accelerated and increased, resulting in an increased tumor incidence. More recently XPC has also been linked to functions outside of NER since XPC deficient mice show a divergent tumor spectrum compared to other NER deficient mouse models. Multiple in vivo and in vitro experiments indicate that XPC appears to be involved in the initiation of several DNA damage-induced cellular responses. XPC seems to function in the removal of oxidative DNA damage, redox homeostasis and cell cycle control. We hypothesize that this combination of increased oxidative DNA damage sensitivity, disturbed redox homeostasis together with inefficient cell cycle control mechanisms are causes of the observed increased cancer susceptibility in oxygen exposed tissues. Such a phenotype is absent in other NER-deficient mice, including Xpa.
authors.affiliation: National Institute of Public Health and the Environment, Laboratory for Health Protection Research, Bilthoven, The Netherlands.
authors.forename: Joost P M
authors.initials: JP
authors.lastname: Melis
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
mesh_terms: D000375:Aging; D000818:Animals; D059447:Cell Cycle Checkpoints; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000209:etiology*; D020641:Polymorphism, Single Nucleotide; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C086984:XPC protein, human