Tumor-prone phenotype of the DDB2-deficient mice

Abstract

DDB2 is an essential subunit of the damaged-DNA recognition factor DDB, which is involved in global genomic repair in human cells. Moreover, DDB2 is mutated in the repair-deficiency disease xeroderma pigmentosum (Group E). Expression of DDB2 in human cells is induced by P53, BRCA1 and by ionizing radiation. The DDB2 protein associates with transcriptional activator and coactivator proteins. In addition, DDB2 in conjunction with DDB1 associates with cullin 4A and the Cop9/signalosome. We generated a mouse strain deficient for DDB2 (DDB2À/À). Consistent with the human disease (XP-E), the DDB2À/À mice were susceptible to UV-induced skin carcinogenesis. We observed a significant difference in the initial rate of cyclobutane pyrimidine dimer (CPD)-removal from the skin following UV irradiation. Also, the DDB2-deficient mice exhibited a significantly reduced life span compared to their wild-type littermates. Moreover, unlike other XP-deficient mice, the DDB2-deficient mice developed spontaneous malignant tumors at a high rate between the ages of 20 and 25 months. The observations suggest that, in addition to DNA repair, the other interactions of DDB2 are significant in its tumor suppression function.

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

“…The tumor spectrum was quite broad, but consistent with the broad expression pattern of DDB2, i.e. lymphomas, lung tumors, breast and cervical carcinomas were found [77]. A clear UV cancer-prone phenotype was found in Ddb2 +/− mice, providing evidence for a gene dosage effect for Ddb2 [76], [77] and [78].…”

“…lymphomas, lung tumors, breast and cervical carcinomas were found [77]. A clear UV cancer-prone phenotype was found in Ddb2 +/− mice, providing evidence for a gene dosage effect for Ddb2 [76], [77] and [78]. In addition, a transgenic mouse model ectopically expressing Ddb2 was generated, in which enhanced expression of the protein delayed the tumor phenotype of the mice and repair of both CPDs and 6-4PP was improved in dermal fibroblasts [78].…”

“…Furthermore, it has recently been shown [75] that in human XPE cells DDB2 first targets and accelerates repair of 6-4 PPs as well. Mice with a disruption of this gene (Ddb2 −/− mice) were generated recently [76], [77] and [78] and apart from the expected skin tumor development upon UVirradiation, these mice have a pronounced spontaneous cancer phenotype. A significantly reduced life span was found possibly owing to a high incidence of developing "spontaneous" tumors at later stages of life (between 20 and 25 months; [77]).…”

Nucleotide Excision Repair and Cancer

“…In 2005 Itoh et al andYoon et al independently generated a strain of DDB2 -/-mice (Itoh,2006;Itoh et al,2004;Yoon et al,2005). The latter group reported that DDB2 -/-mice show a decrease in spontaneous survival (n=10) compared to wild type (Yoon et al,2005).…”

p21 Cooperates with DDB2 Protein in Suppression of Ultraviolet Ray-induced Skin Malignancies

“…Damaged DNA-binding protein 2 (DDB2), a subunit of the damaged DNA-binding protein DDB, encoded by the XP-E gene, plays important roles in both NER and apoptosis following exposure to UV irradiation (1)(2)(3). Ddb2 Ϫ/Ϫ mice develop UV-induced skin cancers with much higher incidence in comparison with wild type (WT) mice (4,5). Enhanced expression of Ddb2 in mice also reduces UV-induced carcinogenesis by delaying the onset of tumor development and also by reducing the number of tumors per mouse, providing further evidence of the role of DDB2 in the inhibition of UV-induced skin tumorigenesis (6).…”