Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DDB is a damage-specific DNA binding protein whose binding activity is absent from a minority of cell strains from individuals with xeroderma pigmentosum Group E, a human hereditary disease characterized by defective nucleotide excision DNA repair and an increased incidence of skin cancer. The binding activity from HeLa cells is associated with polypeptides of M(r) 124,000 and 41,000 as determined by SDS-polyacrylamide gels. This report describes the isolation of full-length human cDNAs encoding each polypeptide of DDB. The predicted peptide molecular masses based on open reading frames are 127,000 and 48,000. When expressed in an in vitro rabbit reticulocyte system, the p48 subunit migrates with an M(r) of 41 kDa on SDS-polyacrylamide gels, similarly to the peptide purified from HeLa cells. There is no significant homology between the derived p48 peptide sequence and any proteins in current databases, and the derived peptide sequence of p127 has homology only with the monkey DDB p127 (98% nucleotide identity and only one conserved amino acid substitution). 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.
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PMID: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. 853 Jan 2

The human diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy are caused by mutations in a set of interacting gene products, which carry out the process of nucleotide excision repair. The majority of the genes have now been cloned and many mutations in the genes identified. The relationships between the distribution of mutations in the genes and the clinical presentations can be used for diagnosis and for understanding the functions and the modes of interaction among the gene products. The summary presented here represents currently known mutations that can be used as the basis for future studies of the structure, function, and biochemical properties of the proteins involved in this set of complex disorders, and may allow determination of the critical sites for mutations leading to different clinical manifestations. The summary indicates where more data are needed for some complementation groups that have few reported mutations, and for the groups for which the gene(s) are not yet cloned. These include the Xeroderma pigmentosum (XP) variant, the trichothiodystrophy group A (TTDA), and ultraviolet sensitive syndrome (UVs) groups. We also recommend that the XP-group E should be defined explicitly through molecular terms, because assignment by complementation in culture has been difficult. XP-E by this definition contains only those cell lines and patients that have mutations in the small subunit, DDB2, of a damage-specific DNA binding protein.
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PMID:A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. 1044 54

We report here a patient (Ops1) with clinical photosensitivity, including pigmented or depigmented macules and patches, and multiple skin neoplasias (malignant melanomas, basal cell carcinomas, and squamous cell carcinomas in situ) in sun-exposed areas. These clinical features are reminiscent of xeroderma pigmentosum. As cells from Ops1 showed normal levels in DNA repair synthesis in vivo (unscheduled DNA synthesis and recovery of RNA synthesis after ultraviolet irradiation), we performed a postreplication repair assay and recovery of replicative DNA synthesis after ultraviolet irradiation to investigate if Ops1 cells belonged to a xeroderma pigmentosum variant pattern. Ops1 cells were normal, but there was an incomplete pattern repair in (6-4) photoproducts in contrast to a normal pattern repair in cis-syn cyclobutane pyrimidine dimers by repair kinetics using the enzyme-linked immunosorbent assay. Moreover, Ops1 cells were defective in a damage-specific DNA binding protein and carried a non-sense mutation in the DDB2 gene. These results suggest that (i) the DDB2 gene is somewhat related to skin carcinogenesis, photoaging skin, and the removal of (6-4) photoproducts; (ii) although it is believed that cyclobutane pyrimidine dimers are the principal mutagenic lesion and (6-4) photoproducts are less likely to contribute to ultraviolet-induced mutations in mammals, Ops1 is one of the ultraviolet-induced mutagenic models induced by (6-4) photoproducts.
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PMID: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. 1046 12

Human DDB (Damaged DNA Binding protein) is a heterodimer of 48 and 127kDa subunits whose activity is absent from cell strains derived from a subset of Xeroderma Pigmentosum (XP) complementation group E individuals (Ddb(-)) [Keeney, S., Wein, H., and Linn, S., (1992). Mut. Res. 273, 49-56]. Whereas in vivo DNA repair appears to be compromised in both Ddb(-) and Ddb(+) XPE cells, DDB activity is not necessary for nucleotide excision repair (NER) in vitro. In this study, the presence of a specific UV-damaged DNA binding activity in mouse cell-free extracts that is comparable to the activity observed in HeLa cells was demonstrated. The mouse DDB2 cDNA, coding for DDB p48 subunit, was cloned and the partial genomic structure of DDB2 was obtained. A search of current databases revealed amino acid sequences of mouse and Drosophila predicted p127 homologues, but not of a Drosophila p48 homologue. The alignment of these higher eukaryotic p127 sequences uncovered the presence of three highly conserved domains in the p127 polypeptides which we hypothesize could function in DNA binding, transcription-transactivation, and protein-protein interaction, respectively.
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PMID:Studies of the murine DDB1 and DDB2 genes. 1071 55

Xeroderma pigmentosum is a photosensitive syndrome caused by a defect in nucleotide excision repair or postreplication repair. Individuals of xeroderma pigmentosum group E (xeroderma pigmentosum E) have a mild clinical form of the disease and their cells exhibit a high level of nucleotide excision repair as measured by unscheduled DNA synthesis, as well as biochemical heterogeneity. Cell strains from one group of xeroderma pigmentosum E patients have normal damage-specific DNA binding activity (Ddb+), whereas others do not (Ddb-). Using a refinement of a previously reported cell fusion complementation assay, the previously assigned Ddb+ xeroderma pigmentosum E strains, XP89TO, XP43TO, and XP24KO, with various phenotypes in DNA repair markers, were reassigned to xeroderma pigmentosum group F, xeroderma pigmentosum variant, and ultraviolet-sensitive syndrome, respectively. The Ddb- xeroderma pigmentosum E strains, XP82TO, and GM02415B, which showed almost normal cellular phenotypes in DNA repair markers, however, remained assigned to xeroderma pigmentosum group E. With the exception of the Ddb+ strain XP89TO, which demonstrated defective nucleotide excision repair, both Ddb- and Ddb+ xeroderma pigmentosum E cells exhibited the same levels of variation in unscheduled DNA synthesis that were seen in normal control cells. By genome DNA sequencing, the two Ddb- xeroderma pigmentosum E strains were shown to have mutations in the DDB2 gene, confirming previous reports for XP82TO and GM02415B, and validating the classification of both cells. As only the Ddb- strains investigated remain classified in the xeroderma pigmentosum E complementation group, it is feasible that only Ddb- cells are xeroderma pigmentosum E and that mutations in the DDB2 gene are solely responsible for the xeroderma pigmentosum E group.
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PMID:Reinvestigation of the classification of five cell strains of xeroderma pigmentosum group E with reclassification of three of them. 1077 87

Damage-specific DNA binding (DDB) activity purifies from HeLa cells as a heterodimer (p127 and p48) and is absent from cells of a subset (Ddb(-)) of xeroderma pigmentosum Group E (XPE) patients. Each subunit was overexpressed in insect cells and purified. Both must be present for the damaged DNA band shift characteristic of the HeLa heterodimer. However, overexpressed p48 peptides containing the mutations found in three Ddb(-) XPE strains are inactive, and wild type p48 restores DDB activity to extracts from a fourth XPE Ddb(-) strain, GM01389, in which compound heterozygous mutations in DDB2 (p48) lead to a L350P change from one allele and a Asn-349 deletion from the other. Although these results indicate that these mutations are each responsible for the loss of DDB activity, they do not affect nuclear localization of p48. In normal fibroblasts, a 4-fold increase in p48 mRNA amount was observed 38 h after UV irradiation, preceding a similar elevation in p48 protein and DDB activity at 48 h, implying that p48 limits DDB activity in vivo. Because DNA repair is virtually complete before 48 h, a role for DDB other than DNA repair is suggested.
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PMID:Human damage-specific DNA-binding protein p48. Characterization of XPE mutations and regulation following UV irradiation. 1077 90

The damaged-DNA binding protein DDB consists of two subunits, DDB1 (127 kDa) and DDB2 (48 kDa). Mutations in the DDB2 subunit have been detected in patients suffering from the repair deficiency disease xeroderma pigmentosum (group E). In addition, recent studies suggested a role for DDB2 in global genomic repair. DDB2 also exhibits transcriptional activity. We showed that expression of DDB1 and DDB2 stimulated the activity of the cell cycle regulatory transcription factor E2F1. Here we show that DDB2 is a cell cycle-regulated protein. It is present at a low level in growth-arrested primary fibroblasts, and after release the level peaks at the G(1)/S boundary. The cell cycle regulation of DDB2 involves posttranscriptional mechanisms. Moreover, we find that an inhibitor of 26S proteasome increases the level of DDB2, suggesting that it is regulated by the ubiquitin-proteasome pathway. Our previous study indicated that the cullin family protein Cul-4A associates with the DDB2 subunit. Because cullins are involved in the ubiquitin-proteasome pathway, we investigated the role of Cul-4A in regulating DDB2. Here we show that DDB2 is a specific target of Cul-4A. Coexpression of Cul-4A, but not Cul-1 or other highly related cullins, increases the ubiquitination and the decay rate of DDB2. A naturally occurring mutant of DDB2 (2RO), which does not bind Cul-4A, is not affected by coexpression of Cul-4A. Studies presented here identify a specific function of the Cul-4A gene, which is amplified and overexpressed in breast cancers.
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PMID:The xeroderma pigmentosum group E gene product DDB2 is a specific target of cullin 4A in mammalian cells. 1156 59

GCN5 is a histone acetyltransferase (HAT) originally identified in Saccharomyces cerevisiae and required for transcription of specific genes within chromatin as part of the SAGA (SPT-ADA-GCN5 acetylase) coactivator complex. Mammalian cells have two distinct GCN5 homologs (PCAF and GCN5L) that have been found in three different SAGA-like complexes (PCAF complex, TFTC [TATA-binding-protein-free TAF(II)-containing complex], and STAGA [SPT3-TAF(II)31-GCN5L acetylase]). The composition and roles of these mammalian HAT complexes are still poorly characterized. Here, we present the purification and characterization of the human STAGA complex. We show that STAGA contains homologs of most yeast SAGA components, including two novel human proteins with histone-like folds and sequence relationships to yeast SPT7 and ADA1. Furthermore, we demonstrate that STAGA has acetyl coenzyme A-dependent transcriptional coactivator functions from a chromatin-assembled template in vitro and associates in HeLa cells with spliceosome-associated protein 130 (SAP130) and DDB1, two structurally related proteins. SAP130 is a component of the splicing factor SF3b that associates with U2 snRNP and is recruited to prespliceosomal complexes. DDB1 (p127) is a UV-damaged-DNA-binding protein that is involved, as part of a complex with DDB2 (p48), in nucleotide excision repair and the hereditary disease xeroderma pigmentosum. Our results thus suggest cellular roles of STAGA in chromatin modification, transcription, and transcription-coupled processes through direct physical interactions with sequence-specific transcription activators and with components of the splicing and DNA repair machineries.
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PMID:Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo. 1156 63

A damage-specific DNA binding protein (DDB) activity is absent from a subset (DDB(-)) of cells from individuals initially classified as group E of xeroderma pigmentosum (XP), a hereditary, photosensitive disease with a high incidence of skin malignancies. In these cases, mutations have been identified in the DDB2 gene (DDB2(-)) that codes for the small subunit, p48, of the DDB heterodimer. In four DDB2(- )strains, neither p48 nor DDB activity were observed before or after UV-irradiation, despite an unusually strong up-regulation of DDB2 mRNA levels after UV-irradiation. In a fifth strain, XP82TO, p48 was detectable and both DDB2 mRNA and p48 levels were more up-regulated after UV-irradiation than in normal primary cells. Moreover, DDB activity also became apparent after irradiation. XP82TO showed very mild clinical manifestations compared with the other DDB(-) patients. These results, coupled with our findings that most, if not all DDB(+) cells classified as XP-E were misclassified, suggests a direct correlation between DDB2 levels and the XP-E phenotype.
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PMID:Abnormal regulation of DDB2 gene expression in xeroderma pigmentosum group E strains. 1170 28

The DDB2 gene, which is mutated in xeroderma pigmentosum group E, enhances global genomic repair of cyclobutane pyrimidine dimers and suppresses UV-induced mutagenesis. Because DDB2 transcription increases after DNA damage in a p53-dependent manner, we searched for and found a region in the human DDB2 gene that binds and responds transcriptionally to p53. The corresponding region in the mouse DDB2 gene shared significant sequence identity with the human gene but was deficient for p53 binding and transcriptional activation. Furthermore, when mouse cells were exposed to UV, DDB2 transcription remained unchanged, despite the accumulation of p53 protein. These results demonstrate direct activation of the human DDB2 gene by p53. They also explain an important difference in DNA repair between humans and mice and show how mouse models can be improved to better reflect cancer susceptibility in humans.
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PMID:p53 Binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice. 1197 58


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