Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition.
A mouse model for the nucleotide excision repair disorder Cockayne syndrome (CS) was generated by mimicking a truncation in the CSB(ERCC6) gene of a CS-B patient. CSB-deficient mice exhibit all of the CS repair characteristics: ultraviolet (UV) sensitivity, inactivation of transcription-coupled repair, unaffected global genome repair, and inability to resume RNA synthesis after UV exposure. Other CS features thought to involve the functioning of basal transcription/repair factor TFIIH, such as growth failure and neurologic dysfunction, are present in mild form. In contrast to the human syndrome, CSB-deficient mice show increased susceptibility to skin cancer. Our results demonstrate that transcription-coupled repair of UV-induced cyclobutane pyrimidine dimers contributes to the prevention of carcinogenesis in mice. Further, they suggest that the lack of cancer predisposition in CS patients is attributable to a global genome repair process that in humans is more effective than in rodents.
van der Horst
G T
GT
Medical Genetics Center, Department of Cell Biology and Genetics, Erasmus University Rotterdam, The Netherlands.
van Steeg
H
H
Berg
R J
RJ
van Gool
A J
AJ
de Wit
J
J
Weeda
G
G
Morreau
H
H
Beems
R B
RB
van Kreijl
C F
CF
de Gruijl
F R
FR
Bootsma
D
D
Hoeijmakers
J H
JH
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D003057:Cockayne Syndrome / Q000235:genetics* / Q000503:physiopathology; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics; D004260:DNA Repair / Q000502:physiology* / Q000528:radiation effects; D045643:DNA Repair Enzymes; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016296:Mutagenesis / Q000502:physiology; D010787:Photosensitivity Disorders / Q000235:genetics / Q000503:physiopathology; D000075223:Poly-ADP-Ribose Binding Proteins; D012097:Repressor Proteins / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology* / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects; D014764:Viral Proteins / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins
D000075223:Poly-ADP-Ribose Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins; D004265:DNA Helicases; C078673:ERCC6 protein, human; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes