Effects of XPD mutations on ultraviolet-induced apoptosis in relation to skin cancer-proneness in repair-deficient syndromes.
To understand the relationship between DNA repair, apoptosis, transcription, and cancer-proneness, we have studied the apoptotic response and the recovery of RNA synthesis following ultraviolet C and ultraviolet B irradiation in nucleotide excision repair deficient diploid fibroblasts from the cancer-prone xeroderma pigmentosum (XP) syndrome patients and the non-cancer-prone trichothiodystrophy (TTD) patients. Analysis of four XPD and four TTD/XPD fibroblast strains presenting different mutations on the XPD gene has shown that XPD cells are more sensitive to ultraviolet-induced apoptosis than TTD/XPD cells, and this response seems to be modulated by the type and the location of the mutation on the XPD gene. Moreover, the other xeroderma pigmentosum fibroblast strains analyzed (groups A and C) are more sensitive to undergo apoptosis after ultraviolet irradiation than normal human fibroblasts, showing that the cancer-proneness of xeroderma pigmentosum patients is not due to a deficiency in the ultraviolet-induced apoptotic response. We have also found that cells from transcription-coupled repair deficient XPA, XPD, TTD/XPD, and Cockayne's syndrome patients undergo apoptosis at lower ultraviolet doses than transcription-coupled repair proficient cells (normal human fibroblasts and XPC), indicating that blockage of RNA polymerase II at unrepaired lesions on the transcribed strand is the trigger. Moreover, XPD and XPA cells are more sensitive to ultraviolet-induced apoptosis than trichothiodystrophy and Cockayne's syndrome fibroblasts, suggesting that both cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone on the transcribed strand trigger apoptosis. Finally, we show that apoptosis is directly proportional to the level of inhibition of transcription, which depends on the density of ultraviolet-induced lesions occurring on transcribed sequences.
Queille
S
S
Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, Institut André Lwoff, IFR 2249, Villejuif, France.
Drougard
C
C
Sarasin
A
A
Daya-Grosjean
L
L
D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D000013:Congenital Abnormalities / Q000235:genetics; D004265:DNA Helicases; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000528:radiation effects; D020022:Genetic Predisposition to Disease; D006197:Hair / Q000002:abnormalities; D006801:Humans; D009154:Mutation / Q000502:physiology*; D011506:Proteins / Q000235:genetics*; D012867:Skin / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics*; D014157:Transcription Factors; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics; D051759:Xeroderma Pigmentosum Group D Protein
D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human