Disease relevance of DDB2

• Mutations in the human DDB2 gene generate the E subgroup of xeroderma pigmentosum (XP-E) [1].
• Mutations in the DDB2 gene have been correlated with the hereditary disease xeroderma pigmentosum group E. We have investigated the proximal promoters of the DDB genes, both of which are G/C-rich and do not contain a TATA box [2].
• Mutations in the DDB2 gene inactivate UV-DDB in individuals from complementation group E of xeroderma pigmentosum (XP-E), an autosomal recessive disease characterized by sun sensitivity, severe risk for skin cancer and defective nucleotide excision repair [3].
• Hepatitis B virus X protein associated with UV-DDB1 induces cell death in the nucleus and is functionally antagonized by UV-DDB2 [4].
• In contrast, overexpressing DDB2 in DDB2-depleted cells with recombinant adenovirus, which carries ddb2 cDNA, markedly inhibited the extent of UV-induced activation of DNA fragmentation factor, and caspase-3 [5].

High impact information on DDB2

• Here, we show that DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1 [6].
• These results suggest that the distinct UV response of the DDB2 and CSA complexes is involved in diverse mechanisms of NER [6].
• The mice exhibited significantly enhanced skin carcinogenesis in response to UV-irradiation, and cells from the DDB2(-/-) mice were abnormally resistant to killing by the radiation and had diminished UV-induced, p53-mediated apoptosis [7].
• Mutations in the human DDB2 gene give rise to xeroderma pigmentosum group E, a disease characterized by increased skin tumorigenesis in response to UV-irradiation [7].
• DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen [7].

Chemical compound and disease context of DDB2

• The DDB2 gene, which is mutated in xeroderma pigmentosum group E, enhances global genomic repair of cyclobutane pyrimidine dimers and suppresses UV-induced mutagenesis [8].

Biological context of DDB2

• To better define the role of DDB2 in the cellular response to DNA damage, we purified all four forms of DDB2 and analyzed their DNA binding properties and their effects on mammalian nucleotide excision repair [9].
• Besides confirming that the true XP-E phenotype is DDB(-), resulting from defects in a single gene, DDB2, our results identify the functional domains of the corresponding p48 protein [10].
• Hence, HBx-mediated cell death can be relieved by increased levels of DDB2, an effect that is not observed with a naturally occurring mutant of DDB2 that lacks DDB1-binding activity [4].
• BRCA1 transcriptionally regulates damaged DNA binding protein (DDB2) in the DNA repair response following UV-irradiation [11].
• Antisense abrogation of BRCA1 expression abrogates upregulation of DDB2 after UVC or cisplatin exposure [11].

Anatomical context of DDB2

• Transient expression analysis in HeLa cells using a luciferase reporter system indicated the presence of core promoters located within 292 bp (DDB1) and 220 bp (DDB2) upstream of the putative transcription initiation sites [2].
• The cisplatin-resistant cell line (HR3) exhibits enhanced expression of DDB2 and cross-resistance to UV-induced activation of apoptosis and caspases [12].
• E6 fibroblasts exhibited markedly reduced basal and induced levels of mRNA encoding DDB2, another protein implicated in early events in global NER [13].
• In contrast, E6 or E6/E7 keratinocytes possessed basal DDB2 mRNA levels that were not significantly altered relative to control cells, although little induction occurred following UV radiation [13].
• We show that the nuclear levels of DDB1 and DDB2 are tightly regulated in hepatocytes [14].

Associations of DDB2 with chemical compounds

• In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product [15].
• The mutants also demonstrated increased sensitivity to UV irradiation, methyl methanesulfonate and hydrogen peroxide treatment, indicating that AtUV-DDB2 is also involved in DNA repair [16].
• Significantly, overexpression of c-Abl increased tyrosine phosphorylation of DDB2 and suppressed UV-DDB activity [17].
• Global genomic repair (GGR) of cyclobutane pyrimidine dimers was significantly increased in the DDB2 expressing cells in comparison to controls, demonstrating that p53 wt protein itself is not directly required for efficient GGR [18].

Physical interactions of DDB2

• Xeroderma pigmentosum complementation group E protein (XPE/DDB2): purification of various complexes of XPE and analyses of their damaged DNA binding and putative DNA repair properties [9].

Regulatory relationships of DDB2

• Accordingly, the elimination of cFLIP by antisense oligonucleotides suppresses DDB2 protection [12].
• Depletion of the elevated DDB2 in HR3 cells sensitizes Fas-inducing antibody-induced and TNF-alpha-induced apoptosis [12].
• We showed that expression of DDB1 and DDB2 stimulated the activity of the cell cycle regulatory transcription factor E2F1 [19].
• DDB2 is one such gene that is regulated by p53 at both the basal and UV inducible levels [18].

Other interactions of DDB2

• UV-DDB comprises two subunits, products of the DDB1 and DDB2 genes, respectively [20].
• Most likely mechanism of this p53 action is through its downstream effector protein, DDB2 [21].
• Loss of BRCA1-dependent DDB2 repair function may contribute to cancer susceptibility and cellular sensitivity to DNA damage [11].
• Cross-resistance to death ligand-induced apoptosis in cisplatin-selected HeLa cells associated with overexpression of DDB2 and subsequent induction of cFLIP [12].
• Restoration of DDB2 function also enhanced the recruitment of XPC to DNA damage sites in situ and increased the global repair of cyclobutane pyrimidine dimer from the genome [22].

Analytical, diagnostic and therapeutic context of DDB2

• Using a fluorescence in situ hybridization technique, the DDB p127 locus (DDB1) was assigned to the chromosomal location 11q12-q13, and the DDB p48 locus (DDB2) to 11p11-p12 [23].
• To test this hypothesis, we conducted a case-control study of 1010 patients with incident lung cancer and 1011 cancer-free controls and genotyped two DDB2 single nucleotide polymorphisms (SNPs) (rs830083 and rs3781620) that are in linkage disequilibrium with other untyped SNPs [24].
• Immunoprecipitation confirmed that Cul4A interacts with DDB1 and also associates with DDB2 [25].
• OsUV-DDB2 (65 kDa) was much larger than human UV-DDB2, but immunoprecipitation and gel mobility shift assay suggested that OsUV-DDB2 is a plant counterpart of UV-DDB2 [26].

References