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

Jan De Boer, Harry Van Steeg, Rob J.W. Berg, Johan Garssen, Jan De Wit, Conny T.M. Van Oostrum, Rudolph B. Beems, Gijsbertus T.J. Van Der Horst, Coen F. Van Kreijl, Frank R. De Gruijl, Dirk Bootsma, Jan H.J. Hoeijmakers, Geert Weeda

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

64 Citaten (Scopus)


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 ~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 clear 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.

Originele taal-2Engels
Pagina's (van-tot)3489-3494
Aantal pagina's6
TijdschriftCancer Research
Nummer van het tijdschrift14
StatusGepubliceerd - 15 jul. 1999
Extern gepubliceerdJa


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