Abnormal regulation of DDB2 gene expression in xeroderma pigmentosum groupE strains

A damage-specific DNA binding protein (DDB) activity is absent from a subse t (DDB-) of cells from individuals initially classified as group E of xerod erma pigmentosum (XP), a hereditary, photosensitive disease with a high inc idence of skin malignancies. In these cases, mutations have been identified in the DDB2 gene (DDB2(-)) that codes for the small subunit, p48, of the D DB heterodimer. In four DDB2(-) strains, neither p48 nor DDB activity were observed before or after UV-irradiation, despite an unusually strong up-reg ulation 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-regulat ed after UV-irradiation than in normal primary cells. Moreover, DDB activit y also became apparent after irradiation. XP82TO showed very mild clinical manifestations compared with the other DDB- patients. These results, couple d with our findings that most, if not all DDB+ cells classified as XP-E wer e misclassified, suggests a direct correlation between DDB2 levels and the XP-E phenotype.