Mouse model for the DNA repair/basal transcription disorder trichotiodystrophy reveals cancer predisposition

Patients with the nucleotide excision repair (NER) disorder xeroderma pigme ntosum (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 heli case subunit of the dually functional DNA repair/basal transcription comple x TFIIH. The pleiotropic disease phenotype is hypothesized to be, in part, derived from a repair defect causing UV sensitivity and, in part, from a su btle, viable basal transcription deficiency accounting for the cutaneous, d evelopmental, and the typical brittle hair features of TTD. To understand t he relationship between deficient NER and tumor susceptibility, we used a m ouse model for TTD that mimics an XPD point mutation of a TTD patient in th e mouse germline. Like the fibroblasts from the patient, mouse cells exhibi t a partial NER defect, evident from the reduced UV-induced DNA repair synt hesis (residual repair capacity similar to 25%), limited recovery of RNA sy nthesis after UV exposure, and a relatively mild hypersensitivity to cell k illing by UV or 7,12-dimethylbenz[a]anthracene. In accordance with the cell ular studies, TTD mice exhibit a modestly increased sensitivity to UV-induc ed inflammation and hyperplasia of the skin. In striking contrast to the hu man syndrome, TTD mice manifest a clear susceptibility to UV- and 7,12-dime thylbenz[a]anthracene-induced skin carcinogenesis, albeit not as pronounced as the totally NER-deficient XPA mice. These findings open up the possibil ity that TTD is associated with a so far unnoticed cancer predisposition an d support the notion that a NER deficiency enhances cancer susceptibility. These findings have important implications for the etiology of the human di sorder and for the impact of NER on carcinogenesis.