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 reco very of RNA synthesis following ultraviolet C and ultraviolet B irradiation in nucleotide excision repair deficient diploid fibroblasts from the cance r-prone xeroderma pigmentosum (XP) syndrome patients and the non-cancer-pro ne trichothiodystrophy (TTD) patients. Analysis of four XPD and four TTD/XP D fibroblast strains presenting different mutations on the XPD gene has sho wn 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 pig mentosum fibroblast strains analyzed (groups A and C) are more sensitive to undergo apoptosis after ultraviolet irradiation than normal human fibrobla sts, 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 (norma l 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 bo th cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone on the trans cribed strand trigger apoptosis. Finally, we show that apoptosis is directl y proportional to the level of inhibition of transcription, which depends o n the density of ultraviolet-induced lesions occurring on transcribed seque nces.