UMLS:C0043346 - FACTA Search

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Query: UMLS:C0043346 (xeroderma pigmentosum)
2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human autosomal recessive disease, xeroderma pigmentosum (XP), can result from mutations in any one of seven genes, designated XPA through XPG. Of these, the XPB and XPD genes encode proteins that are subunits of a general transcription factor, TFIIH, involved in both nucleotide excision repair (NER) and initiation of mRNA transcription by RNA polymerase II. In humans, mutation of the XPB or XPD gene impairs NER, resulting in hyper-sensitivity to sunlight and greatly increased skin tumor formation. However, no transcription deficiency has been demonstrated in either XP-B or XP-D. We have employed an optimized cell-free RNA transcription assay to analyze transcription activity of XP-B and XP-D. Although the growth rate was normal, the XP-B and XP-D cells contained reduced amounts of TFIIH. Extracts prepared from XP-B and XP-D lymphoblastoid cells exhibited similar transcription activity from the adenovirus major late promoter when compared to that in extracts from normal cells. Thus, we conclude that the XP-B and XP-D lymphoblastoid cells do not have impaired RNA transcription activity. We consider the possible consequences of the reduced cellular content of TFIIH for the clinical symptoms in XP-B or XP-D patients, and discuss a 'conditional phenotype' that may involve an impairment of cellular function only under certain growth conditions.
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PMID:Competent transcription initiation by RNA polymerase II in cell-free extracts from xeroderma pigmentosum groups B and D in an optimized RNA transcription assay. 942 33

The human gene XPB, defective in xeroderma pigmentosum patients complementation group B, encodes a DNA helicase involved in several DNA metabolic pathways, including DNA repair and transcription. The high conservation of this gene has allowed the cloning of homologs in various species, such as mouse, yeast and Drosophila. Not much information on the molecular basis of nucleotide excision repair in plants is available, but these organisms may have similar mechanisms to other eukaryotes. A homolog of XPB was isolated in Arabidopsis thaliana by using polymerase chain reaction (PCR) with degenerate oligonucleotides based on protein domains which are conserved among several species. Screening of an Arabidopsis cDNA library led to the identification and isolation of a cDNA clone with 2670 bp encoding a predicted protein of 767 amino acids, denoted araXPB. Genomic analysis indicated that this is a nuclear single copy gene in plant cells. Northern blot with the cDNA probe revealed a major transcript which migrated at approx. 2,800 b, in agreement with the size of the cDNA isolated. The araXPB protein shares approximately 50% identical and 70% conserved amino acids with the yeast and human homologs. The plant protein maintains all the functional domains found in the other proteins, including nuclear localization signal, DNA-binding domain and helicase motifs, suggesting that it might also act as part of the RNA transcription apparatus, as well as nucleotide excision repair in plant cells.
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PMID:Cloning of a cDNA from Arabidopsis thaliana homologous to the human XPB gene. 952 67

Adenovirus type 12 (Ad12) infection of human cells induces four chromosomal fragile sites corresponding to the U1 small nuclear RNA (snRNA) genes (the RNU1 locus), the U2 snRNA genes (RNU2), the U1 snRNA pseudogenes (PSU1), and the 5S rRNA genes (RN5S). Ad12-induced fragility of the RNU2 locus requires U2 snRNA transcriptional regulatory elements and viral early functions but not viral replication or integration, or chromosomal sequences flanking the RNU2 locus. We now show that Ad12 cannot induce the RNU1, RNU2, or PSU1 fragile sites in Saos-2 cells lacking the p53 and retinoblastoma (Rb) proteins but that viral induction of fragility is rescued in these cells when the expression of wild-type p53 or selected hot-spot mutants (i.e., V143A, R175H, R248W, and R273H) is restored by transient expression or stable retroviral transduction. We also observed weak constitutive fragility of the RNU1 and RNU2 loci in cells belonging to xeroderma pigmentosum complementation groups B and D (XPB and XPD) which are partially defective in the ERCC2 (XPD) and ERCC3 (XPB) helicase activities shared between the repairosome and the RNA polymerase H basal transcription factor TFIIH. We propose a model for Ad12-induced chromosome fragility in which interaction of p53 with the Ad12 E1B 55-kDa transforming protein (and possibly E4orf6) induces a p53 gain of function which ultimately perturbs the RNA polymerase II basal transcription apparatus. The p53 gain of function could interfere with chromatin condensation either by blocking mitotic shutdown of U1 and U2 snRNA transcription or by phenocopying global or local DNA damage. Specific fragilization of the RNU1, RNU2, and PSU1 loci could reflect the unusually high local concentration of strong transcription units or the specialized nature of the U1 and U2 snRNA transcription apparatus.
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PMID:Adenovirus type 12-induced fragility of the human RNU2 locus requires p53 function. 955 7

Nucleotide excision repair (NER) is an important cellular defense mechanism which protects the integrity of the genome by removing DNA damage caused by UV-light or chemical agents. In humans, defects in the NER pathway result in the disease xeroderma pigmentosum (XP) which is characterized by increased UV-sensitivity, with increased propensity for skin cancer, and an array of developmental abnormalities. Some XP patients exhibit, in addition, symptoms of Cockayne's syndrome (CS) and trichothiodystrophy (TTD), which are characterized by increased UV-sensitivity, without increased cancer incidence, and an array of developmental abnormalities. Some NER genes, including the DNA helicases XPB and XPD, have been shown to function in transcription as well as repair, by virtue of being an integral part of the transcription initiation factor TFIIH. This dual function may account for the above-mentioned wide pleiotropy of phenotypes associated with defects in NER genes, and may explain why some XP patients exhibit developmental abnormalities in addition to XP symptoms. To date, only five XPB patients with three different mutations in the XPB gene have been reported. One of these mutations is a C to A transversion at the splice site at the beginning of the last exon, which resulted in a frameshift throughout the last exon. This patient shows combined clinical symptoms of XP and CS. The recent cloning of the repB gene, the Dictyostelium discoideum homolog of XPB, allowed us to generate a similar C-terminal mutation in the Dictyostelium, in order to test whether the defect in this NER gene has an effect on growth or development. To this end, we have constructed a C-terminal deletion repB mutant in Dictyostelium. To avoid the possibility that a null mutant would be lethal, we used direct homologous recombination to create a 46 amino acid C-terminal deletion mutant. Indeed, we were unable to obtain mutants with a longer 95 amino acid deletion. The repB delta C46 mutants showed an increased sensitivity to UV-light, but a normal pattern of UV-induced expression of repair genes, and no immediately obvious defect in either growth rate or development. The results suggest that the associated developmental defects in the human XPB patients may be due to mutations in another gene.
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PMID:A mutation in repB, the dictyostelium homolog of the human xeroderma pigmentosum B gene, has increased sensitivity to UV-light but normal morphogenesis. 976 92

The marine demosponge Geodia cydonium encodes a gene, termed GCXPB, which displays 62% identity to the human XPB/ERCC-3 gene that specifically corrects the repair defect in xeroderma pigmentosum and in Cockayne's syndrome. The cDNA was isolated and characterized the deduced aa sequence, XPB_GEOCY, with the calculated size of 91,541 Da comprises the characteristic domains found in the related helicases. Phylogenetic tree analysis revealed that the sponge sequence is grouped to the metazoan related XPB/ERCC-3 polypeptides. Northern Blot analyses have been performed with sponge samples collected at different depths, thus exposed to different intensities of UV sunlight in the field. The intensity of the 2.6 kb band, corresponding to the transcripts of the sponge GCXPB gene was highest in those biotopes, which are closer to the surface of the sea, lower were the expressions in animals from a cave or from depths of 22 to 35 m. Controlled laboratory studies revealed that after irradiation of specimens with 300 or 1000 J/m2 UVB light a dose-dependent increase of the steady-state level of GCXPB occurs, values up to 29-fold with respect to the controls which were kept in the dark have been determined. In parallel, the DNA integrity in the sponge samples was measured using the sensitive Fast Micromethod assay. The data revealed that the degree of strand DNA breaks paralleled the increase of expression of the GCXPB gene. From these data it is concluded that the XPB/ERCC-3-like gene in the sponge G. cydonium is UV light-inducible and hence might be used as biomarker for UV light exposure in the field.
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PMID:Expression of the human XPB/ERCC-3 excision repair gene-homolog in the sponge Geodia cydonium after exposure to ultraviolet radiation. 987 88

The genetic disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS) exhibit deficiencies in the repair of UV-induced DNA damage. CS fibroblasts retain proficient nucleotide excision repair (NER) of inactive (or bulk) DNA, but are deficient in the transcription-coupled repair (TCR) of active genes. In contrast, XP complementation group C (XP-C) fibroblasts retain proficient TCR, but are deficient in bulk DNA repair. The remaining NER-deficient XP groups exhibit deficiencies in both repair pathways. Ad5HCMVsp1lacZ is a recombinant adenovirus vector that is unable to replicate in human fibroblasts, but can efficiently infect and express the beta-galactosidase reporter gene in these cells. We have examined the host cell reactivation (HCR) of beta-galactosidase activity for UV-irradiated Ad5HCMVsp1lacZ in non-irradiated and UV-irradiated normal, XP-B, XP-C, XP-D, XP-F, XP-G, CS-A and CS-B fibroblasts. HCR of beta-galactosidase activity for UV-irradiated Ad5HCMVsp1lacZ was reduced in non-irradiated cells from each of the repair-deficient groups examined (including XP-C) relative to that in non-irradiated normal cells. Prior irradiation of cells with low UV fluences resulted in an enhancement of HCR for normal and XP-C strains, but not for the remaining XP and CS strains. HCR of the UV-damaged reporter gene in UV-irradiated XP and CS strains was similar to measurements of TCR reported previously for these cells. These results suggest that UV treatment results in an induced repair of UV-damaged DNA in the transcribed strand of an active gene in XP-C and normal cells through an enhancement of TCR or a mechanism which involves the TCR pathway.
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PMID:UV-enhanced reactivation of a UV-damaged reporter gene suggests transcription-coupled repair is UV-inducible in human cells. 993 45

As part of TFIIH, XPB and XPD helicases have been shown to play a role in nucleotide excision repair (NER). Mutations in these subunits are associated with three genetic disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). The strong heterogeneous clinical features observed in these patients cannot be explained by defects in NER alone. We decided to look at the transcriptional activity of TFIIH from cell lines of XP individuals. We set up an immunopurification procedure to isolate purified TFIIH from patient cell extracts. We demonstrated that mutations in two XP-B/CS patients decrease the transcriptional activity of the corresponding TFIIH by preventing promoter opening. The defect of XPB in transcription can be circumvented by artificial opening of the promoter. Western blot analysis and enzymatic assays indicate that XPD mutations affect the stoichiometric composition of TFIIH due to a weakness in the interaction between XPD-CAK complex and the core TFIIH, resulting in a partial reduction of transcription activity. This work, in addition to clarifying the role of the various TFIIH subunits, supports the current hypothesis that XP-B/D patients are more likely to suffer from transcription repair syndromes rather than DNA repair disorders alone.
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PMID:Mutations in XPB and XPD helicases found in xeroderma pigmentosum patients impair the transcription function of TFIIH. 1006 1

The human XPB DNA helicase is a subunit of the DNA repair/basal transcription factor TFIIH, involved in early steps of the nucleotide excision repair pathway. Two distinct clinical phenotypes, xeroderma pigmentosum associated with Cockayne's syndrome (XP/CS) and trichothiodystrophy (TTD), can be due to mutations in the XPB gene. In the present work, we studied cellular DNA repair properties of skin fibro-blasts from two patients mutated in the XPB gene: an XP/CS patient cell (XPCS2BA) with a T296C (F99S) transition and a TTD patient cell (TTD6VI) exhibiting an A355C (T119P) transversion. Both cells are clearly associated with different levels of alterations in their response to UV light. To establish the relationship between the relative expression level of these two alleles and DNA repair properties, we transfected SV40-transformed XPCS2BA (XPCS2BASV) cells with a plasmid (pTTD6VI) carrying the XPB-A355C cDNA and examined DNA repair properties after UV irradiation (cell survival, unscheduled DNA synthesis and kinetics of photoproduct removal) in stable transfectants. We isolated three clones, which express the XPB-A355C gene (Cl-5) or the XPB-T296C gene (Cl-14) or both genes (Cl-19). This con-stitutes a model system allowing us to correlate the relative expression levels of the XPB-A355C (TTD) and XPB-T296C (XP/CS) genes with various DNA repair properties. Overexpression of the XPB-A355C (TTD) gene in an XP/CS cell gives rise to a cellular phenotype of increased repair similar to that of TTD6VI cells, while equal expression of the two mutated genes leads to an intermediate cellular phenotype between XP/CS and TTD.
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PMID:The relative expression of mutated XPB genes results in xeroderma pigmentosum/Cockayne's syndrome or trichothiodystrophy cellular phenotypes. 1033 46

The tumor suppressor gene product p53 can bind to and inhibit the helicase activity of the multisubunit transcription-repair factor TFIIH. We previously reported that p53-mediated apoptosis is attenuated in primary human fibroblasts from individuals with Xeroderma Pigmentosum (XP) that harbor mutations in the TFIIH DNA helicases XPD or XPB. In this study we show that apoptosis is reduced and delayed in three XPD lymphoblastoid cell lines (LCLs), but not in an XPD heterozygote LCL, after exposure to doxorubicin, a DNA-damaging agent and topoisomerase II inhibitor frequently used in cancer therapy. Apoptosis was assessed by quantitation of Annexin V binding to exposed phosphatidylserine residues and by caspase-mediated cleavage of Poly(ADP)Ribose Polymerase (PARP). Apoptosis induced by doxorubicin was suppressed in LCLs retrovirally transduced with the Human Papillomavirus 16 E6 oncoprotein, consistent with the hypothesis that this is a p53-dependent process. PARP cleavage was not delayed in XPD LCLs in response to anti-Fas (CD95) antibody-mediated apoptosis, thus, the defect in the apoptotic pathway in these cells lies upstream of caspase activation. Similar changes in the expression of apoptosis-effector genes, p53, and p53-responsive genes p21Cip1/WAF-1/Sid1 (p21), gadd45, bcl-2 and bax were observed in normal and XPD LCLs after treatment with doxorubicin, indicating that delayed apoptosis was not a consequence of defective transcription of these genes. Thus, our studies provide further support to the hypothesis that XPD and p53 can functionally interact in a p53-mediated apoptotic pathway.
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PMID:Drug-induced apoptosis is delayed and reduced in XPD lymphoblastoid cell lines: possible role of TFIIH in p53-mediated apoptotic cell death. 1046 15

To provide an explanation of some clinical features observed within rare xeroderma pigmentosum (XP) patients and to further define the role of XPB, XPD, and cdk7, the three enzymatic subunits of TFIIH, in the transcription reaction, we have examined two defined enzymatic steps: phosphodiester bond formation and promoter escape. We provide evidence that the XPB helicase plays a dominant role in initiation, whereas the XPD helicase plays a minor contributing role in this step. The cyclin-activating kinase subcomplex of TFIIH improves the efficiency of initiation, but this involves only the structural contributions of cyclin-activating kinase rather than enzymatic activity. We demonstrate that XPB patient-derived mutants in TFIIH suffer from defects in initiation. Moreover, mutant analysis shows that in addition to its crucial role in initiation, the XPB helicase plays a critical enzymatic role in the promoter escape, whereas XPD plays an important structural role in the promoter escape process. Finally, using patient-derived mutations in TFIIH, we demonstrate deficiencies in promoter escape for both mutants of the class that suffer from combined xeroderma pigmentosum/Cockayne's syndrome.
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PMID:Distinct roles for the helicases of TFIIH in transcript initiation and promoter escape. 1064 10

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