Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition.
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.
MGC-Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands.
J
J
de Boer
H
H
van Steeg
R J
RJ
Berg
J
J
Garssen
J
J
de Wit
C T
CT
van Oostrum
R B
RB
Beems
G T
GT
van der Horst
C F
CF
van Kreijl
F R
FR
de Gruijl
D
D
Bootsma
J H
JH
Hoeijmakers
G
G
Weeda
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000483:Alleles; D000818:Animals; D003057:Cockayne Syndrome / Q000235:genetics; D004265:DNA Helicases; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology / Q000528:radiation effects; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D006201:Hair Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D007057:Ichthyosis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D017354:Point Mutation; D011506:Proteins / Q000235:genetics / Q000502:physiology; D011836:Radiation Tolerance / Q000235:genetics; D012867:Skin / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D019473:Transcription Factors, TFII; D014158:Transcription, Genetic / Q000235:genetics*; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics; D051759:Xeroderma Pigmentosum Group D Protein
D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D051758:Transcription Factor TFIIH; D015127:9,10-Dimethyl-1,2-benzanthracene; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; C497293:Ercc2 protein, mouse