Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition
1999
textabstractPatients 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.
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