Cellular responses to UV: The role of UV-DDB in DNA repair and microarray analysis of skin cancer patients.

摘要

UV-damaged DNA binding (UV-DDB) is composed of two subunits, DDB1 (p127) and DDB2 (p48). In humans, mutations in the DDB2 gene that inactivate the UV-DDB occur in complementation group E of xeroderma pigmentosum (XP), an autosomal recessive disease characterized by sun sensitivity, severe risk for skin cancer, and defective nucleotide excision repair (NER). When cells are exposed to UV, p53 activates DDB2 transcription, which leads to increased levels of UV-DDB. In vitro, UV-DDB binds to cyclobutane pyrimidine dimers (CPDs), 6-4 photoproducts, and other DNA lesions. UV-DDB is deficient in many rodent tissues, however, transfection of DDB2 conferred UV-DDB to hamster cells. UV-DDB enhanced the removal of CPDs from genomic DNA and from the nontranscribed strand of an expressed gene. We have defined the role of DDB2 in the global genomic repair of CPDs and showed that the expression of DDB2 suppressed UV-induced mutations arising from the nontranscribed strand, but had no effect on cellular UV sensitivity. This disassociation between UV sensitivity and mutagenesis lead us to search for UV-DDB deficiencies in skin cancer patients and to examine their transcriptional response to UV. We have found approximately 1200 genes that are UV-inducible in human lymphocytes, and a subset of genes that may correlate with skin cancer patients. Both DDB1 and DDB2 interact with many proteins, and we have also found that DDB2 is phosphorylated by c-Abl tyrosine kinase to regulate the specificity of UV-DDB for UV damage. The DDB1 gene is strongly conserved among eukaryotes, but there is no such conservation for DDB2. We suggest that UV-DDB may have roles that are distinct from DNA repair.