Abnormal regulation of DDB2 gene expression in xeroderma pigmentosum group E strains.

A damage-specific DNA binding protein (DDB) activity is absent from a subset (DDB ) of cells from individuals initially classified as group E of xeroderma pigmentosum (XP), a hereditary, photosensitive disease with a high incidence of skin malignancies. In these cases, mutations have been identified in the DDB2 gene (DDB2) that codes for the small subunit, p48, of the DDB heterodimer. In four DDB2 strains, neither p48 nor DDB activity were observed before or after UV-irradiation, despite an unusually strong up-regulation of DDB2 mRNA levels after UV-irradiation. In a fifth strain, XP82TO, p48 was detectable and both DDB2 mRNA and p48 levels were more up-regulated after UV-irradiation than in normal primary cells. Moreover, DDB activity also became apparent after irradiation. XP82TO showed very mild clinical manifestations compared with the other DDB patients. These results, coupled with our findings that most, if not all DDB + cells classified as XP-E were misclassified, suggests a direct correlation between DDB2 levels and the XP-E phenotype.