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)

The SSL1 locus was identified as a trans-acting suppressor that restores HIS4 expression despite a stem-loop structure in the 5'-UTR. SSL1 encodes an essential protein of 52 kD with features characteristic of a protein with multiple zinc fingers. The mechanism of SSL1 suppression is not related to altering his4 transcription or removing the stem-loop sequence from the 5'-UTR; rather, 3- to 5-fold increases in His4 translational expression are observed indicating a post-transcriptional mechanism for SSL1 suppression. SSL1 suppressor mutants that are conditional for growth have altered polysome profiles at the restrictive temperature, and their cell-free extracts are thermolabile in their ability to translate exogenously added mRNA. In addition, the mechanism of suppression appears to be specific for stem-loop structures placed near the 5' end of the message as opposed to a stem-loop located at a downstream position in the 5'-UTR. These observations suggest a role for this protein in promoting translation initiation presumably at the level of ribosomal binding to mRNA. Surprisingly, SSL1 suppressor mutations that are shown to confer an in vivo and in vitro defect in translation initiation also rendered yeast hypersensitive to UV irradiation. This latter phenotype was observed previously with a mutation in the SSL2 suppressor gene, which encodes the yeast homolog of the human gene ERCC-3, for which a defective form causes xeroderma pigmentosum. In light of the related effects of mutations in the SSL1 and SSL2 genes, the encoded proteins may functionally interact both to promote DNA repair and perform an essential function during translation initiation.
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PMID:SSL1, a suppressor of a HIS4 5'-UTR stem-loop mutation, is essential for translation initiation and affects UV resistance in yeast. 134 Apr 63

We showed previously that the xeroderma pigmentosum group A complementing (XPAC) protein involved in the DNA excision repair pathway contains a zinc-finger motif and is localized in the nucleus of normal human cells. For detailed structural and functional analyses of the XPAC protein, we constructed various XPAC cDNAs by site-directed mutagenesis and isolated permanent cell lines expressing mutant proteins. Immunofluorescent analysis of these lines indicated that the nuclear localization signal is located in the region encoded by Exon 1, especially centered at amino acids 30-42. A UV survival study showed that regions from Exons 2 through 6 were essential for DNA repair function, but that Exon 1 was not. Interestingly, deletion of the glutamic acid cluster in the region encoded by Exon 2 resulted in a dramatic loss of DNA repair activity. Furthermore, replacements of each of the 4 cysteines supposed to form a zinc-finger structure in the region encoded by Exon 3 by serine or glycine resulted in similar levels of loss of repair activity. These results suggest that all 4 cysteines forming a zinc-finger structure and also the glutamic acid cluster are important for DNA repair function.
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PMID:Mutational analysis of the structure and function of the xeroderma pigmentosum group A complementing protein. Identification of essential domains for nuclear localization and DNA excision repair. 160 84

Xeroderma pigmentosum (XP), a human autosomal recessive disorder, is characterized by extreme sensitivity to sunlight and high incidence of skin cancers. XP cells are defective in the incision step of excision repair of DNA damaged by ultraviolet light. Cell fusion studies have defined seven XP complementation groups, XP-A to XP-G. Similar genetic complexity of excision repair is observed in the yeast Saccharomyces cerevisiae. Mutations in any one of five yeast genes, RAD1, RAD2, RAD3, RAD4, and RAD10, cause a total defect in incision and an extreme sensitivity to ultraviolet light. Here we report the characterization of the yeast RAD14 gene. The available rad14 point mutant is only moderately ultraviolet-sensitive, and it performs a substantial amount of incision of damaged DNA. Our studies with the rad14 deletion (delta) mutation indicate an absolute requirement of RAD14 in incision. RAD14 encodes a highly hydrophilic protein of 247 amino acids containing zinc-finger motifs, and it is similar to the protein encoded by the human XPAC gene that complements XP group A cell lines.
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PMID:Yeast RAD14 and human xeroderma pigmentosum group A DNA-repair genes encode homologous proteins. 174 Oct 34

We cloned homologs of the human Xeroderma Pigmentosum Group A complementing (XPAC) gene from chicken, Xenopus laevis and Drosophila melanogaster. A comparison of the amino acid sequences of these homologs with that of the human XPAC protein revealed that in the NH2-terminal domain there are only two conserved regions, one of which is presumed to function as the nuclear localization signal, whereas the COOH-terminal domain is highly conserved, the frequency of identical amino acids in all four XPAC proteins being 50%, and the four cysteine residues predicted to form a zinc-finger motif, and three other cysteine residues are all conserved. These results strongly suggest that the COOH-terminal domain containing a zinc-finger motif plays an important role in the function of these proteins.
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PMID:Molecular cloning of human XPAC gene homologs from chicken, Xenopus laevis and Drosophila melanogaster. 176 72

Several data suggest a relationship of poly(ADP-ribose) (PAR) synthesis to DNA repair and the influence of some trace elements on the semiconservative and unscheduled DNA synthesis (UDS). Previously we found certain alterations in the UV-light induced UDS and in the contents of trace elements in the lymphocytes of patients with light sensitive skin disorders. In the recent study in polymorphic light eruption, cutaneous porphyrias and xeroderma pigmentosum the PAR synthesis and zinc, copper and manganese contents in the chromatin of the lymphocytes (measured by neutron activation analysis) were investigated. UV induced PAR synthesis was generally lower in the cells of polymorphic light eruption and especially in xeroderma pigmentosum with a reduced repair capacity whereas in cutaneous porphyrias no difference was observed. Some correlations occurred between the contents of trace elements studied and UDS as well in each group tested. It seems that PAR investigations throw new light upon our understanding of the pathomechanism of photodermatoses.
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PMID:Poly(ADP-ribose)-synthesis and excision repair in light sensitive skin disorders. 209 34

Xeroderma pigmentosum (XP) is an autosomal recessive disease, characterized by a high incidence of sunlight-induced skin cancer. Cells from people with this condition are hypersensitive to ultraviolet because of a defect in DNA repair. There are nine genetic complementation groups of XP, groups A-H and a variant. We have cloned the mouse DNA repair gene that complements the defect of group A, the XPAC gene. Here we report molecular cloning of human and mouse XPAC complementary DNAs. Expression of XPAC cDNA confers ultraviolet-resistance on several group A cell lines, but not on lines of other XP groups. Almost all group A lines tested showed abnormality or absence of XPAC messenger RNAs. These results indicate that a defective XPAC gene causes group A XP. The human and mouse XPAC genes are located on chromosome 9q34.1 and chromosome 4C2, respectively. Human XPAC cDNA encodes a protein of 273 amino acids with a zinc-finger motif.
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PMID:Analysis of a human DNA excision repair gene involved in group A xeroderma pigmentosum and containing a zinc-finger domain. 223 52

In light of recent studies implicating low catalase activities in the pathogenesis of the cancer-prone disease xeroderma pigmentosum (XP) we have measured catalase activity, protein levels, and mRNA concentrations in six XP fibroblast strains and three normal controls. Only one XP strain of complementation group A (XP1223) possessed significantly lower catalase by all three criteria. The other five XP strains (two XP variants, two strains of complementation group D, and one strain of complementation group C) possessed catalase levels which fell into the range of the interindividual variations of normal controls. We further assessed the total enzymatic antioxidant defense status by measuring the levels of copper, zinc, and manganese superoxide dismutase and glutathione peroxidase. None of these enzymes showed significant deviations from controls in XP cells. Our results do not support the notion that a deficient enzymatic antioxidant defense facilitates the establishment of a prooxidant state in XP upon exposure to near-UV. However, they do not argue against the participation of active oxygen in near-UV-induced carcinogenesis in XP.
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PMID:Antioxidant enzymes in xeroderma pigmentosum fibroblasts. 334 84

Synthesis of the low molecular weight, thiol-rich, metal-binding metallothioneins (MTS) is undetectable in normal human (NF) or xeroderma pigmentosum (XP) fibroblasts grown in the absence of excess ZnCl2. Addition of 200 microM ZnCl2 to the growth medium produces an increased MT synthesis rising from the basal rate to a rate at least 50-fold greater than basal rate within 7 h. MT induction kinetics in confluent and in exponentially growing subconfluent monolayers were indistinguishable. Zn2+-mediated MT induction is sensitive to actinomycin D suggesting that the induction process is under transcriptional control. Ultraviolet light irradiation causes a dose-dependent inactivation of Zn2+-mediated MT induction in both NF and XP cells. Post-irradiation incubation of UV-irradiated cells using liquid holding techniques leads to reactivation of Zn2+-mediated MT induction in NF cells but not in XP cells. These findings suggest the utility of MT induction produce transcription-terminating lesions, and (b) in evaluating cellular repair capacity for this class of DNA lesions.
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PMID:Ultraviolet light inactivation of zinc-mediated metallothionein induction in normal and repair-deficient human cells. 712 93

The XPA (xeroderma pigmentosum group A) gene encodes a protein of 273 amino acids with a zinc finger motif. The human XPA cDNA was placed in an Escherichia coli expression vector for the synthesis of the recombinant XPA protein. The molecular weight of the wild-type protein was about 40 kDa in SDS-PAGE. Microinjection of the wild-type protein specifically restored the defect of UV-induced unscheduled DNA synthesis in XP-A cells. Thus, the bacterially expressed XPA protein retains biochemical properties identical to those of natural sources. The wild-type protein binds preferentially to UV-, cis-diamminedichloroplatinum(II) (cisplatin)- or osmium tetroxide (OsO4)-damaged DNA as assayed by retention on nitrocellulose filters. In addition, the data from atomic absorption and UV-CD spectra revealed that the wild-type protein is a zinc metalloprotein with secondary structure. Furthermore, the mutant protein, of which the cysteine-103 residue in the zinc finger motif was replaced with serine, has a vastly different protein conformation resulting in a loss of XP-A correcting and DNA-binding activities. These findings indicate that the XPA protein is a zinc-binding protein with affinity for various DNA damages, and a cysteine residue in the C4-type zinc finger motif is indispensable for normal protein conformation.
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PMID:The XPA protein is a zinc metalloprotein with an ability to recognize various kinds of DNA damage. 752

All the reported Japanese patients with group A xeroderma pigmentosum (XP) have two or three mutations at codon 116 in exon 3, codon 228 in exon 6, and the splicing acceptor site of intron 3 of XP group A complementing (XPAC) gene. A homozygote (XP39OS) with a nonsense mutation at codon 228 has less severe neurological abnormalities than patients with the splicing mutation at the acceptor site of intron 3. As homozygotes for the nonsense mutation at codon 116, which truncates a carboxyl-terminal site of XPAC protein at an early part of its zinc-finger domain, have not been reported previously, the possible severity of associated neurological abnormalities was not known. We report a group A XP patient, XP18OS, who had neurological abnormalities which were more severe than those in patients homozygous for the splicing mutation. The polymerase chain reaction product from exon 3 of the patient's XPAC gene was digested completely into three fragments by MseI restriction endonuclease. Thus, the patient was homozygous for the mutation at codon 116.
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PMID:Severe neurological abnormalities associated with a mutation in the zinc-finger domain in a group A xeroderma pigmentosum patient. 794 12


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