Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA.
Xeroderma pigmentosum patients with a defect in the nucleotide-excision repair gene XPA are characterized by, for example, a > 1,000-fold higher risk of developing sunlight-induced skin cancer. Nucleotide-excision repair (NER) is involved in the removal of a wide spectrum of DNA lesions. The XPA protein functions in a pre-incision step, the recognition of DNA damage. To permit the functional analysis of the XPA gene in vivo, we have generated XPA-deficient mice by gene targeting in embryonic stem cells. The XPA-/-mice appear normal, at least until the age of 13 months. XPA-/-mice are highly susceptible to ultraviolet (UV)-B-induced skin and eye tumours and to 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumours. We conclude that the XPA-deficient mice strongly mimic the phenotype of humans with xeroderma pigmentosum.
de Vries
A
A
Department of Immunology, University of Utrecht, The Netherlands.
van Oostrom
C T
CT
Hofhuis
F M
FM
Dortant
P M
PM
Berg
R J
RJ
de Gruijl
F R
FR
Wester
P W
PW
van Kreijl
C F
CF
Capel
P J
PJ
van Steeg
H
H
Verbeek
S J
SJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005134:Eye Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D011836:Radiation Tolerance; D012878:Skin Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000235:genetics / Q000473:pathology; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene