Disease relevance of DDB1

• The DDB1 subunit is a target for the hepatitis B virus X protein (HBx) [1].
• The p127 subunit (DDB1) of the UV-DNA damage repair binding protein is essential for the targeted degradation of STAT1 by the V protein of the paramyxovirus simian virus 5 [2].
• The V proteins of the mumps virus, human parainfluenza virus 2 (hPIV2), and measles virus have also been found to interact with DDB1 in GST-fusion protein selection assays using in vitro transcribed and translated DDB1 [3].
• 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 [4].
• Interestingly, whereas HBx induces cell death in both HepG2 and Huh-7 hepatoma cell lines, it enhances HBV replication only in HepG2 cells, suggesting that the two activities involve distinct DDB1-dependent pathways [5].

Psychiatry related information on DDB1

• GRAND ROUNDS: An Atypical Progressive Dementia in a Male Carrier of the Fragile X Premutation: An Example of Fragile X-Associated Tremor/Ataxia Syndrome [6].

High impact information on DDB1

• Our results strongly suggest that ubiquitylation plays a critical role in the transfer of the UV-induced lesion from UV-DDB to XPC [7].
• Here, we show that DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1 [8].
• The human UV-damaged DNA-binding protein Ddb1 associates with cullin 4 ubiquitin ligases implicated in nucleotide excision repair (NER) [9].
• UV-damaged DNA-binding activity (UV-DDB) is deficient in some xeroderma pigmentosum group E individuals due to mutation of the p48 gene, but its role in DNA repair has been obscure [10].
• We found that UV-DDB is also deficient in cell lines and primary tissues from rodents [10].

Chemical compound and disease context of DDB1

• XPE binding factor (XPE-BF) is deficient in a subset of patients from xeroderma pigmentosum complementation group E. Binding activity copurifies with a 125 kDa polypeptide (p125) that binds to DNA damaged by ultraviolet (UV) radiation and many other agents [11].
• One of the two factors, designated XPE binding factor, is deficient in complementation group E of xeroderma pigmentosum, an inherited disease characterized by defective repair of DNA damaged by ultraviolet radiation, cisplatin, and other agents [12].

Biological context of DDB1

• 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 [13].
• Binding of HBx to DDB1 interferes with cell growth and viability in culture and has been implicated in the establishment of viral infection [1].
• 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 [14].
• Given that the loss of monoubiquitinated histone H2A at the sites of UV-damaged DNA is associated with decreased global genome repair in XP-E cells, this study suggests that histone modification, mediated by the XPE factor, facilitates the initiation of NER [15].
• To the best of our knowledge, this is the first occasion that a dwarf phenotype has been found to be associated with a UV-DDB2 mutation in either plants or animals [16].

Anatomical context of DDB1

• We show that the nuclear levels of DDB1 and DDB2 are tightly regulated in hepatocytes [17].
• However, overexpression of DDB1 did not augment UV-damaged-DNA recognition activity in human HeLa, hamster V79, or rat PC12 cells [18].
• This activity is defective in at least some xeroderma pigmentosum group E (XP-E) patients; microinjection of the UV-DDB protein into their fibroblasts corrects nucleotide excision repair (NER) [19].
• Human tumor cell lines selected for resistance to cisplatin showed more efficient DNA repair and increased expression of XPE binding factor [12].
• As late as day 19, there was a continued cellular response from cisplatin, as evidenced by decreased levels of XPE binding factor in extracts from the patient's peripheral blood lymphocytes [20].

Associations of DDB1 with chemical compounds

• The interaction of V and DDB1 involves the carboxyl-terminal domain of V in that either deletion of the V carboxyl-terminal domain or substitution of the cysteine residues (C189, C193, C205, C207, C210, C214, and C217) in the zinc-binding domain with alanine was able to disrupt binding to DDB1 [3].
• In contrast to previous reports, the DNA damage binding protein was shown to recognize cyclobutane pyrimidine dimers in addition to a nonphotoreactivable lesion(s), most likely the pyrimidine-pyrimidone (6-4) photoproduct [21].
• Significantly, overexpression of c-Abl increased tyrosine phosphorylation of DDB2 and suppressed UV-DDB activity [22].
• The interaction between X protein and XAP-1 protein was verified by immunoprecipitation of yeast cell lysates expressing both proteins and by in vitro mixing with X protein expressed as a glutathione S-transferase fusion protein and XAP-1 protein either in HeLa cell extracts or synthesized by in vitro translation [23].
• These results suggest that XPE binding factor may be responsible, at least in part, for the development of cisplatin resistance in human tumors and that the mechanism may be increased DNA repair [12].

Physical interactions of DDB1

• The UV-DDB complex is a component of the newly identified cullin 4A-based ubiquitin E3 ligase, DDB1-CUL4A(DDB2) [15].
• Our studies suggest that L2DTL and PCNA interact with CUL4/DDB1 complexes and are involved in CDT1 degradation after DNA damage [24].
• L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage [24].
• In animal cells, DDB1 interacts with histone acetyltransferase complexes [25].
• A 127-kDa protein (UV-DDB) binds to the cytoplasmic domain of the Alzheimer's amyloid precursor protein [26].

Regulatory relationships of DDB1

• Hepatitis B virus X protein associated with UV-DDB1 induces cell death in the nucleus and is functionally antagonized by UV-DDB2 [13].
• Binding of SV5-V to DDB1 may serve another function, since SV5-V shows a decreased ability to induce STAT1 degradation in cells expressing reduced amounts of DDB1 [1].
• Second, mutations in the N and C termini of V which abolish the binding of V to DDB1 also prevent V from blocking interferon (IFN) signaling [2].
• DDB1-depleted cells accumulate DNA double-strand breaks in widely dispersed regions throughout the genome and have activated ATM and ATR cell cycle checkpoints [27].
• We show that the interaction with DDB1 mediates Vpr-induced apoptosis and UNG2/SMUG1 degradation and impairs the repair of UV-damaged DNA, which could account for G(2) arrest and apoptosis [28].

Other interactions of DDB1

• UV-DDB comprises two subunits, products of the DDB1 and DDB2 genes, respectively [15].
• First, the V protein of an SV5 mutant which fails to target STAT1 for degradation does not bind DDB1 [2].
• This complex includes both STAT1 and STAT2, and the damaged DNA binding protein, DDB1 [29].
• Moreover, we provide evidence for a physical association between Cul4A, DDB1, and Skp2 [30].
• All Rubulavirus V proteins tested require cellular DDB1 to target STATs for degradation but differ in the use of Roc1, which is essential for mumps V STAT3 targeting [31].

Analytical, diagnostic and therapeutic context of DDB1

• 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 [32].
• Immunoprecipitation confirmed that Cul4A interacts with DDB1 and also associates with DDB2 [33].
• Northern blot analysis demonstrates an abundant expression of the DDB1 transcript in the retina suggesting a functional role for DDB1 in this tissue [34].
• Sequence analysis revealed a single A(931)-to-T(931) base transversion in the coding sequence of the DDB1 gene in the hp-1 mutant plants [35].
• Translocation of a UV-damaged DNA binding protein into a tight association with chromatin after treatment of mammalian cells with UV light [19].

References