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

Abstract

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.

• Authors: J de Boer, H van Steeg, R J Berg, J Garssen, J de Wit, C T van Oostrum, R B Beems, G T van der Horst, C F van Kreijl, F R de Gruijl, D Bootsma, J H Hoeijmakers, G Weeda
• Journal: Cancer research (Cancer Res) Vol. 59 Issue 14 Pg. 3489-94 (Jul 15 1999) ISSN: 0008-5472 [Print] United States
• PMID: 10416615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Proteins
• Transcription Factors
• Transcription Factors, TFII
• Transcription Factor TFIIH
• 9,10-Dimethyl-1,2-benzanthracene
• DNA Helicases
• Xeroderma Pigmentosum Group D Protein
• ERCC2 protein, human
• Ercc2 protein, mouse

Topics

• 9,10-Dimethyl-1,2-benzanthracene (toxicity)
• Alleles
• Animals
• Cockayne Syndrome (genetics)
• DNA Helicases
• DNA Repair (genetics)
• DNA-Binding Proteins
• Disease Models, Animal
• Fibroblasts (pathology, radiation effects)
• Gene Targeting
• Genetic Predisposition to Disease
• Growth Disorders (genetics, pathology)
• Hair Diseases (genetics, pathology)
• Humans
• Hyperplasia
• Ichthyosis (genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Neoplastic Syndromes, Hereditary (genetics)
• Point Mutation
• Proteins (genetics, physiology)
• Radiation Tolerance (genetics)
• Skin (pathology, radiation effects)
• Skin Neoplasms (chemically induced, genetics)
• Transcription Factor TFIIH
• Transcription Factors (deficiency, genetics, physiology)
• Transcription Factors, TFII
• Transcription, Genetic (genetics)
• Ultraviolet Rays
• Xeroderma Pigmentosum (genetics)
• Xeroderma Pigmentosum Group D Protein