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.