Photocarcinogenesis and inhibition of intercellular adhesion molecule 1 expression in cells of DNA-repair-defective individuals

AUTOR(ES)

Ahrens, Constanze

FONTE

The National Academy of Sciences of the USA

RESUMO

Cells from patients with xeroderma pigmentosum complementation group D (XP-D) and most patients with trichothiodystrophy (TTD) are deficient in excision repair of ultraviolet (UV) radiation-induced DNA damage. Although in both syndromes this defect is based on mutations in the same gene, XPD, only XP-D, not TTD, individuals have an increased risk of skin cancer. Since the reduction in DNA repair capacity is similar in XP-D and TTD patients, it cannot account for the difference in skin cancer risk. The features of XP-D and TTD might therefore be attributable to differences in the immune response following UV-irradiation, a factor which is presumed to be important for photocarcinogenesis. We have measured the capacity of UVB radiation to inhibit expression of the immunological key molecule intercellular adhesion molecule 1 (ICAM-1) in cells from three healthy individuals in comparison to cells from three XP-D and three TTD patients. Cells from XP-D patients, but not from TTD patients, exhibited an increased susceptibility to UVB radiation-induced inhibition of ICAM-1 expression. Transfection of XP-D cells with the wild-type XPD cDNA, but not with XPC cDNA, corrected this abnormal phenotype. Thus, the skin cancer risk in DNA repair-defective individuals correlated with the susceptibility of their cells to UVB radiation-induced inhibition of ICAM-1 expression, rather than with their defect in DNA repair. The XPD protein has dual roles: in DNA repair and transcription. The transcriptional role might be important for the control of expression of immunologically relevant genes and thereby contribute to the skin cancer risk of a DNA-repair-deficient individual.

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