Tumor suppressor p53 controls cell cycle progression and apoptosis following DNA damage, thus minimizing carcinogenesis. Mutations in the human DDB2 gene generate the E subgroup of xeroderma pigmentosum (XP-E). We report here that XP-E strains are defective in UV irradiation-induced apoptosis due to severely reduced basal and UV-induced p53 levels. These defects are restored by infection with a p53 cDNA expression construct or with a DDB2 expression construct if and only if it contains intron 4, which includes a nonmutated p53 consensus-binding site. We propose that both before and after UV irradiation, DDB2 directly regulates p53 levels, while DDB2 expression is itself regulated by p53.Xeroderma pigmentosum (XP) is a rare hereditary disease with a high incidence of UV light-induced skin cancers (7). Of eight known XP groups, XP-E has unique clinical and cellular phenotypes. For example, XP-E patients suffer from skin cancers without typical xerosis, and cell strains from XP-E patients are not abnormally sensitive to UV and have normal levels of DNA repair synthesis in vivo (26,27). XP-E is caused by mutations in the DDB2 gene (26, 27, 37), which encodes the small subunit, p48 DDB2 , of a heterodimeric damage-specific DNA binding protein (DDB) that also contains p127 DDB1 (10). Expression of the DDB2 gene is perturbed by UV irradiation. In a human normal diploid fibroblast strain, IMR-90, after an initial reduction in DDB activity, there is a two-to fourfold increase in DDB2 mRNA levels 36 h after UV irradiation followed by a peaking of p48 DDB2 protein and DDB activity 48 h after irradiation (27, 37). Since nucleotide excision repair (NER) is all but complete 48 h after UV irradiation (13), and since NER reconstitution studies have shown that DDB is not required for NER in vitro (1, 35), the direct function, if any, of DDB in DNA repair is unclear. In XP-E cell strains, p48 DDB2 protein and DDB activity are undetectable after UV irradiation (except in strain XP82TO), yet DDB2 mRNA levels are abnormally high both before (2-to 4-fold) and after (11-to 37-fold) UV irradiation (27). However, the regulation of DDB2 induction after UV damage is poorly understood.The tumor suppressor protein p53 is important in cellular responses to DNA damage and mutations in the TP53 gene are frequently identified in human cancers (12,41,45). For example, 40 to 60% of skin cancers have mutations in TP53, suggesting that abnormal p53 function is crucial in perhaps a majority of human skin cancers (8,9,16). Activation of p53 in response to DNA damage occurs as a result of a rapid increase in its levels through stabilization of the protein and a number of posttranslational modifications. These changes allow p53 to mediate transcriptional activation of a number of genes (3,30,40). The CDKN1A (WAF1) and BAX genes, whose products trigger cell cycle arrest and apoptosis, respectively, are regulated in this manner (20,41).While the degradation of p53 is known to be regulated by MDM2-mediated ubiquitination and consequent targeting for prote...