Alternative titles; symbols
HGNC Approved Gene Symbol: DDB2
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38): 11:47,214,454-47,239,217 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | Xeroderma pigmentosum, group E, DDB-negative subtype | 278740 | Autosomal recessive | 3 |
The p48 gene (DDB2) is required for expression of an ultraviolet radiation (UV)-damaged DNA-binding activity and is disrupted by mutations in the subset of xeroderma pigmentosum group E (XPE; 278740) cells that lack this activity, DDB-negative XPE (Hwang et al., 1999).
Dualan et al. (1995) isolated full-length human cDNAs encoding the 2 polypeptides of DDB: p127 (DDB1; 600045) and p48 (DDB2).
By fluorescence in situ hybridization, Dualan et al. (1995) assigned the DDB2 gene to chromosome 11p12-p11.
Nichols et al. (1996) found that overexpression of p48 in insect cells greatly increased DDB activity in the cells, especially if p127 was jointly overexpressed. These results demonstrated that p48 is required for DNA-binding activity.
Hwang et al. (1998) demonstrated that expression of human DDB2 activated DNA binding by DDB1 in several hamster and human cell lines. No such effects were observed following expression of DDB2 containing single amino acid substitutions from XPE cells that lacked binding activity. DDB2 formed a complex with DDB1 either bound to UV-damaged DNA or in free solution. Activation of DDB1 occurred by a 'hit-and-run' mechanism, since the presence of DDB2 was not required for subsequent binding of DDB1 to UV-damaged DNA. Hamster cells that failed to express Ddb2, which contains a WD motif with homology to proteins that reorganize chromatin, also failed to efficiently repair cyclobutane pyrimidine dimers in nontranscribed DNA. Hwang et al. (1998) concluded that DDB2 plays a role in repairing lesions that would otherwise remain inaccessible in nontranscribed chromatin.
In human cells, efficient global genomic repair of DNA damage induced by UV radiation requires the p53 tumor suppressor (191170). Hwang et al. (1999) showed that p48 mRNA levels strongly depend on basal p53 expression and increase further after DNA damage in a p53-dependent manner. Furthermore, like p53 -/- cells, XPE cells are deficient in global genomic repair. These results identified p48 as a link between p53 and the nucleotide excision repair apparatus.
Shiyanov et al. (1999) stated that the DDB complex has a transcriptional function in conjunction with E2F1 (189971), in addition to its role in the DNA damage response. By coimmunoprecipitation analysis of HeLa cell nuclear extracts, followed by mass spectrometric analysis and sequencing of novel tryptic peptides, they found that the DDB complex interacted with CUL4A (603137), a predicted E3 ubiquitin ligase. The DDB-CUL4A complex bound UV-damaged DNA.
Tang et al. (2000) found that UV-damaged DNA-binding activity (UV-DDB) is deficient in cell lines and primary tissues from rodents. Transfection of p48 conferred UV-DDB to hamster cells and enhanced removal of cyclobutane pyrimidine dimers (CPDs) from genomic DNA and from the nontranscribed strand of an expressed gene. Expression of p48 suppressed UV-induced mutations arising from the nontranscribed strand but had no effect on cellular UV sensitivity. The results defined the role of p48 in DNA repair, demonstrated the importance of CPDs in mutagenesis, and suggested how rodent models can be improved to better reflect cancer susceptibility in humans.
By immunoprecipitation analysis of HeLa cells, Groisman et al. (2003) identified DDB2 and CSA (609412) as components of similar but distinct protein complexes. Both DDB2 and CSA interacted with DDB1 (600045), a component of both complexes. Cullin-4A (CUL4A; 603137), ROC1 (RBX1; 603814), and all the subunits of the COP9 signalosome (e.g., COPS2; 604508) were also present in both complexes. Following UV irradiation, the DDB2 complex bound tightly to chromatin in a UV-dependent manner and initiated global genome repair, whereas the CSA complex bound to RNA polymerase II and initiated transcription-coupled repair. The COP9 signalosome in each complex differentially regulated cullin-based ubiquitin ligase activity in response to UV irradiation.
Using HeLa and U2OS human cell lines, Balbo Pogliano et al. (2017) found that DDB2 recruited the histone methyltransferase ASH1L (607999) to CPD lesions in DNA caused by UV irradiation. In turn, ASH1L trimethylated histone H3 (see 602810) lys4 (H3K4me3), which promoted stable docking of XPC (613208) at nucleosomes near CPD sites and initiation of NER activity. Coimmunoprecipitation analysis showed that DDB2 and ASH1L interacted directly, and knockdown of either protein via short interfering RNA abrogated UV-dependent increase in H3K4me3, caused dysregulated XPC recruitment in NER complexes at nucleosomes, and delayed CPD excision and DNA repair.
Nichols (1995) reported that RT-PCR mutation analysis in 5 fibroblast XPE strains (2 without and 3 with DDB-binding activity) covering 90 to 99% of the sequence of DDB1 revealed no mutations. Approximately 40% of DDB2 had been sequenced and had revealed no mutations in 2 fibroblast XPF strains (278760).
Nichols et al. (1996) identified mutations in the DDB2 gene in the 3 known cases of DDB-negative XPE. No mutations were found in the cDNA of the 127-kD subunit.
Rapic-Otrin et al. (2003) described several genetically unrelated patients with XPE, each carrying 2 mutated alleles for DDB2, causing either a single amino acid change (see 600811.0004), a protein truncation, or internal deletion. These defects resulted in a severe decrease of detectable p48 protein, abolished interaction with the p127 subunit, and produced a deficiency in UV-DDB binding activity.
In 1 of the 3 known cases of DDB-negative xeroderma pigmentosum, complementation group E (278740), Nichols et al. (1996) found an A-to-G transition causing a lys244-to-glu (K244E) amino acid change in the 48-kD subunit of the DDB heterodimer.
Shiyanov et al. (1999) stated that the K244E mutation in DDB2 interferes with the DDB1 (600045)-DDB2 interaction in damaged DNA binding assays and also affects transcriptional activity.
In 2 of the 3 known cases of DDB-negative xeroderma pigmentosum, complementation group E (278740), Nichols et al. (1996) found a G-to-A transition that caused an arg273-to-his (R273H) amino acid change in the 48-kD subunit of the DDB protein.
Shiyanov et al. (1999) stated that the R273H and lys244-to-glu (K244E; 600811.0001) mutations in DDB2 interfere with the DDB1 (600045)-DDB2 interaction in damaged DNA binding assays and also affect transcriptional activity. They showed that the R273H mutation, but not the K244E mutation, also abrogated interaction of the DDB complex with CUL4A (603137).
Itoh et al. (1999) studied a 62-year-old Japanese woman who was first recognized to be photosensitive at the age of about 20 (see XPE; 278740). There were no complications during pregnancy, labor, or delivery. The parents were consanguineous. She showed average development. At the time of study, she had clinical sensitivity to UV light including pigmented or depigmented macules and patches on the face, neck, chest, and limbs, especially the dorsa of the hands. The sun-exposed skin showed slight dryness. Furthermore, she had multiple skin neoplasms (5 malignant melanomas and 14 basal cell carcinomas on the face, and 2 squamous cell carcinomas in situ on her forearm and leg). No mutation of DDB1 (600045) was detected; the DDB2 cDNA showed homozygosity for a C-to-T transition at nucleotide 937 in exon 7 of genomic DNA, generating a nonsense mutation in CGA (arg) to TGA (stop) at codon 313. This would be expected to produce a protein truncated by 115 amino acids.
In an Italian woman with DDB-negative xeroderma pigmentosum, complementation group E (278740), Rapic-Otrin et al. (2003) identified homozygosity for a 1094G-T transversion in the DDB2 gene, resulting in an asp307-to-tyr (D307Y) substitution.
Balbo Pogliano, C., Gatti, M., Ruthemann, P., Garajova, Z., Penengo, L., Naegeli, H. ASH1L histone methyltransferase regulates the handoff between damage recognition factors in global-genome nucleotide excision repair. Nature Commun. 8: 1333, 2017. [PubMed: 29109511] [Full Text: https://doi.org/10.1038/s41467-017-01080-8]
Dualan, R., Brody, T., Keeney, S., Nichols, A. F., Admon, A., Linn, S. Chromosomal localization and cDNA cloning of the genes (DDB1 and DDB2) for the p127 and p48 subunits of a human damage-specific DNA binding protein. Genomics 29: 62-69, 1995. [PubMed: 8530102] [Full Text: https://doi.org/10.1006/geno.1995.1215]
Groisman, R., Polanowska, J., Kuraoka, I., Sawada, J., Saijo, M., Drapkin, R., Kisselev, A. F., Tanaka, K., Nakatani, Y. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113: 357-367, 2003. [PubMed: 12732143] [Full Text: https://doi.org/10.1016/s0092-8674(03)00316-7]
Hwang, B. J., Ford, J. M., Hanawalt, P. C., Chu, G. Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. Proc. Nat. Acad. Sci. 96: 424-428, 1999. [PubMed: 9892649] [Full Text: https://doi.org/10.1073/pnas.96.2.424]
Hwang, B. J., Toering, S., Francke, U., Chu, G. p48 activates a UV-damaged-DNA binding factor and is defective in xeroderma pigmentosum group E cells that lack binding activity. Molec. Cell. Biol. 18: 4391-4399, 1998. [PubMed: 9632823] [Full Text: https://doi.org/10.1128/MCB.18.7.4391]
Itoh, T., Mori, T., Ohkubo, H., Yamaizumi, M. A newly identified patient with clinical xeroderma pigmentosum phenotype has a non-sense mutation in the DDB2 gene and incomplete repair in (6-4) photoproducts. J. Invest. Derm. 113: 251-257, 1999. [PubMed: 10469312] [Full Text: https://doi.org/10.1046/j.1523-1747.1999.00652.x]
Nichols, A. F., Ong, P., Linn, S. Mutations specific to the xeroderma pigmentosum group E Ddb- phenotype. J. Biol. Chem. 271: 24317-24320, 1996. [PubMed: 8798680] [Full Text: https://doi.org/10.1074/jbc.271.40.24317]
Nichols, A. F. Personal Communication. Berkeley, Calif. 10/4/1995.
Rapic-Otrin, V., Navazza, V., Nardo, T., Botta, E., McLenigan, M., Bisi, D. C., Levine, A. S., Stefanini, M. True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product. Hum. Molec. Genet. 12: 1507-1522, 2003. [PubMed: 12812979] [Full Text: https://doi.org/10.1093/hmg/ddg174]
Shiyanov, P., Nag, A., Raychaudhuri, P. Cullin 4A associates with the UV-damaged DNA-binding protein DDB. J. Biol. Chem. 274: 35309-35312, 1999. [PubMed: 10585395] [Full Text: https://doi.org/10.1074/jbc.274.50.35309]
Tang, J. Y., Hwang, B. J., Ford, J. M., Hanawalt, P. C., Chu, G. Xeroderma pigmentosum p48 gene enhances global genomic repair and suppresses UV-induced mutagenesis. Molec. Cell 5: 737-744, 2000. [PubMed: 10882109] [Full Text: https://doi.org/10.1016/s1097-2765(00)80252-x]