Patients with the nucleotide excision repair (NER) disorder xeroderma pigmentosum (XP) are highly predisposed to develop sunlight-induced skin cancer, in remarkable contrast to photosensitive NER-deficient trichothiodystrophy (TTD) patients carrying mutations in the same XPD gene. XPD encodes a helicase subunit of the dually functional DNA repair/basal transcription complex TFIIH. The pleiotropic disease phenotype is hypothesized to be, in part, derived from a repair defect causing UV sensitivity and, in part, from a subtle, viable basal transcription deficiency accounting for the cutaneous, developmental, and the typical brittle hair features of TTD. To understand the relationship between deficient NER and tumor susceptibility, we used a mouse model for TTD that mimics an XPD point mutation of a TTD patient in the mouse germline. Like the fibroblasts from the patient, mouse cells exhibit a partial NER defect, evident from the reduced UV-induced DNA repair synthesis (residual repair capacity approximately 25%), limited recovery of RNA synthesis after UV exposure, and a relatively mild hypersensitivity to cell killing by UV or 7,12-dimethylbenz[a]anthracene. In accordance with the cellular studies, TTD mice exhibit a modestly increased sensitivity to UV-induced inflammation and hyperplasia of the skin. In striking contrast to the human syndrome, TTD mice manifest a dear susceptibility to UV- and 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis, albeit not as pronounced as the totally NER-deficient XPA mice. These findings open up the possibility that TTD is associated with a so far unnoticed cancer predisposition and support the notion that a NER deficiency enhances cancer susceptibility. These findings have important implications for the etiology of the human disorder and for the impact of NER on carcinogenesis.

*Disease Models, Animal, *Point Mutation, *Transcription Factors, TFII, 0 (Proteins), 0 (Taf6 protein, Drosophila), 0 (Transcription Factors), 0 (Transcription Factors, TFII), 130067-74-2 (ERCC-2 protein), 148710-81-0 (transcription factor TFIIH), 57-97-6 (9,10-Dimethyl-1,2-benzanthracene), 9,10-Dimethyl-1,2-benzanthracene/toxicity, Alleles, Animals, Cockayne Syndrome/genetics, DNA Repair/*genetics, Fibroblasts/pathology/radiation effects, Gene Targeting, Genetic Predisposition to Disease, Growth Disorders/*genetics/pathology, Hair Diseases/*genetics/pathology, Human, Hyperplasia, Ichthyosis/*genetics/pathology, Mice, Mice, Inbred C57BL, Neoplastic Syndromes, Hereditary/*genetics, Proteins/genetics/physiology, Radiation Tolerance/genetics, Skin Neoplasms/chemically induced/*genetics, Skin/pathology/radiation effects, Support, Non-U.S. Gov't, Transcription Factors/deficiency/*genetics/physiology, Transcription, Genetic/*genetics, Ultraviolet Rays, Xeroderma Pigmentosum/genetics
Erasmus MC: University Medical Center Rotterdam

de Boer, J, van Steeg, H, Berg, R.J.W, Garssen, J, de Wit, J, van Oostrom, C.T.M, … Weeda, G. (1999). Mouse model for the DNA repair/basal transcription disorder Trichothiodystrophy reveals cancer predisposition. Retrieved from