PMID- 10416615
OWN - NLM
STAT- MEDLINE
DCOM- 19990812
LR  - 20131121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 59
IP  - 14
DP  - 1999 Jul 15
TI  - Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy
      reveals cancer predisposition.
PG  - 3489-94
AB  - 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.
FAU - de Boer, J
AU  - de Boer J
AD  - MGC-Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The
      Netherlands.
FAU - van Steeg, H
AU  - van Steeg H
FAU - Berg, R J
AU  - Berg RJ
FAU - Garssen, J
AU  - Garssen J
FAU - de Wit, J
AU  - de Wit J
FAU - van Oostrum, C T
AU  - van Oostrum CT
FAU - Beems, R B
AU  - Beems RB
FAU - van der Horst, G T
AU  - van der Horst GT
FAU - van Kreijl, C F
AU  - van Kreijl CF
FAU - de Gruijl, F R
AU  - de Gruijl FR
FAU - Bootsma, D
AU  - Bootsma D
FAU - Hoeijmakers, J H
AU  - Hoeijmakers JH
FAU - Weeda, G
AU  - Weeda G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Transcription Factors, TFII)
RN  - 148710-81-0 (Transcription Factor TFIIH)
RN  - 57-97-6 (9,10-Dimethyl-1,2-benzanthracene)
RN  - EC 3.6.4.- (DNA Helicases)
RN  - EC 3.6.4.12 (Xeroderma Pigmentosum Group D Protein)
RN  - EC 5.99.- (ERCC2 protein, human)
RN  - EC 5.99.- (Ercc2 protein, mouse)
SB  - IM
MH  - 9,10-Dimethyl-1,2-benzanthracene/toxicity
MH  - Alleles
MH  - Animals
MH  - Cockayne Syndrome/genetics
MH  - *DNA Helicases
MH  - DNA Repair/*genetics
MH  - *DNA-Binding Proteins
MH  - *Disease Models, Animal
MH  - Fibroblasts/pathology/radiation effects
MH  - Gene Targeting
MH  - Genetic Predisposition to Disease
MH  - Growth Disorders/*genetics/pathology
MH  - Hair Diseases/*genetics/pathology
MH  - Humans
MH  - Hyperplasia
MH  - Ichthyosis/*genetics/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neoplastic Syndromes, Hereditary/*genetics
MH  - *Point Mutation
MH  - Proteins/genetics/physiology
MH  - Radiation Tolerance/genetics
MH  - Skin/pathology/radiation effects
MH  - Skin Neoplasms/chemically induced/*genetics
MH  - Transcription Factor TFIIH
MH  - Transcription Factors/deficiency/*genetics/physiology
MH  - *Transcription Factors, TFII
MH  - Transcription, Genetic/*genetics
MH  - Ultraviolet Rays
MH  - Xeroderma Pigmentosum/genetics
MH  - Xeroderma Pigmentosum Group D Protein
EDAT- 1999/07/23 00:00
MHDA- 1999/07/23 00:01
CRDT- 1999/07/23 00:00
PHST- 1999/07/23 00:00 [pubmed]
PHST- 1999/07/23 00:01 [medline]
PHST- 1999/07/23 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1999 Jul 15;59(14):3489-94.