Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

During nucleotide excision repair, damaged DNA is incised on both sides of a lesion and an oligomer containing the damage is excised and replaced by repair DNA synthesis. The latter step is accomplished in vitro by proteins that include the DNA polymerase accessory factor PCNA, which binds to DNA ends to initiate repair synthesis. An increased association of PCNA with nuclei occurs after UV irradiation of nonreplicating DNA in normal human fibroblasts, probably following incision of damaged DNA. This property was used to detect the catalysis of nucleotide excision repair incisions in damaged DNA in vivo, by immunostaining of quiescent human fibroblasts with the widely available PC10 antibody. We summarize here a comprehensive survey of PCNA immunostaining in repair-defective xeroderma pigmentosum (XP) cells in comparison to normal cells. XP-A and XP-G cells were completely defective in staining for PCNA 30 min after UV irradiation. This strongly suggests that XPA and XPG proteins are absolutely required in cells before any incisions can be formed in damaged DNA. XP-B, XP-C, XP-D, and XP-F cells showed an intermediate level of staining for PCNA after UV irradiation, indicative of partial incision capacity in those cells. UV-irradiated XP-E and XP-V cells showed normal PCNA immunostaining levels, consistent with evidence that the corresponding factors are not essential for the incision step of repair. The results provide further evidence for the involvement of PCNA in the repair process in vivo and give an alternative to traditional approaches for measurement of nucleotide excision repair capability.
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PMID:Detection of nucleotide excision repair incisions in human fibroblasts by immunostaining for PCNA. 749 31

The ultraviolet light (UV)-responsive element (URE) is an octamer sequence, TGACAACA, that shares homology with cyclic AMP-responsive element and activator protein 1 target sequences. Because URE-binding proteins have been shown to play a role in cellular response to DNA damage, we determined their expression and DNA-binding activities in repair-deficient cells. Of the complementation groups tested, only xeroderma pigmentosum (XP)-C cells induced expression of c-jun after UV irradiation; this correlated with XP-C binding to the URE and resembled the pattern observed with normal human fibroblasts. In other cases either a decrease (XP-A) or no change (XP-D) in URE-binding activities was noticed, which may be associated with decreased c-fos and poor c-jun expression after UV irradiation. That XP-C cells were the only complementation group exhibiting URE-binding activities similar to those of repair-proficient cells points to the possible correlation between proper repair of transcriptionally active genes and the expression and activities of proteins implicated in the cellular response to UV irradiation.
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PMID:Ultraviolet light-responsive element (TGACAACA)-binding proteins in cells of xeroderma pigmentosum patients. 757 98

Xeroderma pigmentosum (XP) is a sun-sensitive, cancer-prone genetic disorder characterized by a defect in nucleotide excision repair. The human nucleotide excision repair and transcription gene ERCC2 is able to restore survival to normal levels after exposure to UV light in XP complementation group D cells. No enhancement of UV survival is seen in groups C, E, F, or G. XP-CS-2 cells are complemented by ERCC2, confirming the reassignment to group D of this combined XP/Cockayne's syndrome patient. Nucleotide sequence analysis of the ERCC2 cDNA from five XP group D cell strains [XP6BE(SV40), XP17PV, XP102LO, A31-27 (a HeLa/XP102LO hybrid), and XP-CS-2] revealed mutations predominantly affecting previously identified functional domains. The mutations include base substitutions resulting in amino acid substitutions, deletions due to splicing alterations, and defects in expression. XP6BE(SV40), XP17PV, XP102LO, and A31-27 all have one allele with an Arg683 to Trp substitution within the putative nuclear location signal. The genetic disorder trichothiodystrophy (which is not cancer-prone) can also result from mutations in the ERCC2 gene, some of which are the same as those found in XP-D. The various clinical presentations can be correlated with the particular mutations found in the ERCC2 locus.
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PMID:Defects in the DNA repair and transcription gene ERCC2 in the cancer-prone disorder xeroderma pigmentosum group D. 758 50

Mutations in the human XPD gene result in a defect in nucleotide excision repair of ultraviolet damaged DNA and cause the cancer-prone syndrome xeroderma pigmentosum (XP). Besides XP, mutations in XPD can cause another seemingly unrelated syndrome, trichothiodystrophy (TTD), characterized by sulfur-deficient brittle hair, ichthyosis, and physical and mental retardation. To ascertain the underlying defect responsible for TTD, we have expressed the TTD mutant proteins in the yeast Saccharomyces cerevisiae and determined if these mutations can rescue the inviability of a rad3 null mutation. RAD3, the S. cerevisiae counterpart of XPD, is required for nucleotide excision repair and also has an essential role in RNA polymerase II transcription. Expression of the wild type XPD protein or the XPD Arg-48 protein carrying a mutation in the DNA helicase domain restores viability to the rad3 null mutation. Interestingly, the XPD variants containing TTD mutations fail to complement the lethality of the rad3 null mutation, strongly suggesting that TTD mutations impair the ability of XPD protein to function normally in RNA polymerase II transcription. From our studies, we conclude that XPD DNA helicase activity is not essential for transcription and infer that TTD mutations in XPD result in a defect in transcription.
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PMID:Lethality in yeast of trichothiodystrophy (TTD) mutations in the human xeroderma pigmentosum group D gene. Implications for transcriptional defect in TTD. 762 61

Nucleotide excision repair is the principal way by which human cells remove UV damage from DNA. Human cell extracts were fractionated to locate active components, including xeroderma pigmentosum (XP) and ERCC factors. The incision reaction was then reconstituted with the purified proteins RPA, XPA, TFIIH (containing XPB and XPD), XPC, UV-DDB, XPG, partially purified ERCC1/XPF complex, and a factor designated IF7. UV-DDB (related to XPE protein) stimulated repair but was not essential. ERCC1- and XPF-correcting activity copurified with an ERCC1-binding polypeptide of 110 kDa that was absent in XP-F cell extract. Complete repair synthesis was achieved by combining these factors with DNA polymerase epsilon, RFC, PCNA, and DNA ligase I. The reconstituted core reaction requires about 30 polypeptides.
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PMID:Mammalian DNA nucleotide excision repair reconstituted with purified protein components. 769 16

The phenotypic consequences of a nucleotide excision repair (NER) defect in man are apparent from three distinct inborn diseases characterized by hypersensitivity of the skin to ultraviolet light and a remarkable clinical and genetic heterogeneity. These are the prototype repair syndrome, xeroderma pigmentosum (XP) (seven genetic complementation groups, designated XP-A to XP-G), Cockayne's syndrome (two groups: CS-A and CS-B) and PIBIDS, a peculiar photosensitive form of the brittle hair disease trichothiodystrophy (TTD, at least two groups of which one equivalent to XP-D). To investigate the mechanism of NER and to resolve the molecular defect in these NER deficiency diseases we have focused on the cloning and characterization of human DNA repair genes. One of the genes that we cloned is ERCC3. It specifies a chromatin binding helicase. Transfection and microinjection experiments demonstrated that mutations in ERCC3 are responsible for XP complementation group B, a very rare form of XP that is simultaneously associated with Cockayne's syndrome (CS). The ERCC3 protein was found to be part of a multiprotein complex (TFIIH) required for transcription initiation of most structural genes and for NER. This defines the additional, hitherto unknown vital function of the gene. This ERCC3 gene and several other NER genes involved in transcription initiation will be discussed.
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PMID:Nucleotide excision repair syndromes: molecular basis and clinical symptoms. 774 58

Nucleotide excision repair (NER)-deficient human cells have been assigned so far to a genetic complementation group by a somatic cell fusion assay and, more recently, by microinjection of cloned DNA repair genes. We describe a new technique, based on the host cell reactivation assay, for the rapid determination of the complementation group of NER-deficient xeroderma pigmentosum (XP), Cockayne's syndrome (CS) and photosensitive trichothiodystrophy (TTD) human cells by cotransfection of a UV-irradiated reporter plasmid with a second vector containing a cloned repair gene. Expression of the reporter gene, either chloramphenicol acetyltransferase (CAT) or luciferase, reflects the DNA repair ability restored by the introduction of the appropriate repair gene. All genetically characterized XP, CS and TTD/XP-D cells tested failed to express the UV-irradiated reporter gene, this reflecting their NER deficiency whereas cotransfection with the repair plasmid expressing a gene specific for the given complementation group increased the enzyme activity to the level reached by normal cells. Selective recovery of both reporter enzyme activities was observed after cotransfection with the XPC gene for the XP17VI cells and with the XPA gene for both XP18VI and XP19VI cells. Using this method, we assigned three new NER-deficient human cells obtained from patients presenting clinical symptoms described as classical XP to either XP group A (XP18VI and XP19VI) and XP group C (XP17VI). Therefore, this technique increases the range of methods now available to determine the complementation group of new NER deficient patients with the advantage, unlike the somatic cell fusion assay or the microinjection procedure, of being simple, rapid, and inexpensive.
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PMID:Development of a new easy complementation assay for DNA repair deficient human syndromes using cloned repair genes. 776 57

A human apurinic/apyrimidinic endonuclease activity, called AP endonuclease I, is missing from or altered specifically in cells cultured from Xeroderma pigmentosum group-D individuals (XP-D cells) (Kuhnlein, U., Lee, B., Penhoet, E. E., and Linn, S. (1978) Nucleic Acids Res. 5,951-960). We have now observed that another nuclease activity, UV endonuclease III, is similarly not detected in XP-D cells and is inseparable from the AP endonuclease I activity. This activity preferentially cleaves the phosphodiester backbone of heavily ultraviolet-irradiated DNA at unknown lesions as well as at one of the phosphodiester bonds within a cyclobutane pyrimidine dimer. The nuclease activities have been purified from mouse cells to yield a peptide of M(r) = 32,000, whose sequence indicates identity with ribosomal protein S3. The nuclease activities all cross-react with immunopurified antibody directed against authentic rat ribosomal protein S3, and, upon expression in Escherichia coli of a cloned rat cDNA for ribosomal protein S3, each of the activities was recovered and was indistinguishable from those of the mammalian UV endonuclease III. Moreover, the protein expressed in E. coli and its activities cross-react with the rat protein antibody. Ribosomal protein S3 contains a potential nuclear localization signal, and the protein isolated as a nuclease also has a glycosylation pattern consistent with a nuclear localization as determined by lectin binding. The unexpected role of a ribosomal protein in DNA damage processing and the unexplained inability to detect the nuclease activities in extracts from XP-D cells are discussed.
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PMID:Implication of mammalian ribosomal protein S3 in the processing of DNA damage. 777 13

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are quite distinct genetic disorders that are associated with defects in excision repair of UV-induced DNA damage. A few patients have been described previously with the clinical features of both disorders. In this paper we describe an individual in this category who has unusual cellular responses to UV light. We show that his cultured fibroblasts and lymphocytes are extremely sensitive to irradiation with UV-C, despite a level of nucleotide excision repair that is 30%-40% that of normal cells. The deficiency is assigned to the XP-D complementation group, and we have identified two causative mutations in the XPD gene: a gly-->arg change at amino acid 675 in the allele inherited from the patient's mother and a -1 frameshift at amino acid 669 in the allele inherited from his father. These mutations are in the C-terminal 20% of the 760-amino-acid XPD protein, in a region where we have recently identified several mutations in patients with trichothiodystrophy.
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PMID:Molecular and cellular analysis of the DNA repair defect in a patient in xeroderma pigmentosum complementation group D who has the clinical features of xeroderma pigmentosum and Cockayne syndrome. 782 73

Individuals affected by the autosomal recessive disease xeroderma pigmentosum (XP) are acutely sensitive to sunlight and predisposed to skin cancer on exposed areas. Cells cultured from XP patients are both UV sensitive and defective in the nucleotide excision repair of damaged DNA. These cellular phenotypes are amenable to experimental strategies employing complementation, an approach previously used to demonstrate the correction of XP-D phenotypes following the introduction of the XPD (ERCC2) gene. In the present study, we have characterized the genomic organization of the XPD (ERCC2) gene and found it to be comprised of 23 exons. These data were helpful in evaluating the functional integrity of alleles in two XP-D cell lines. In cell line GM436 a C-->G transversion was found at nucleotide position 1411 in the XPD (ERCC2) cDNA, a change expected to result in a Leu461Val substitution. Cell line XP67MA carries a C-->T transition in genomic DNA at nucleotide position 2176 in exon 22, introducing the termination codon TAG at amino acid 726. The latter would be expected to produce a protein truncated by 34 amino acids. Although expression of the normal XPD cDNA could be shown to correct the UV sensitivity phenotype in XP-D cells, cDNA constructs bearing either of the two mutations failed to yield complementation. These results confirm the role of ERCC2 in XP-D and illustrate the power of utilizing cellular phenotypes to evaluate the significance of single nucleotide substitutions.
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PMID:Structural and mutational analysis of the xeroderma pigmentosum group D (XPD) gene. 784 2


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