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)

Xeroderma pigmentosum (XP) patients are extremely sensitive to ultraviolet (UV) light and suffer from a high incidence of skin cancers, due to a defect in nucleotide excision repair. The disease is genetically heterogeneous, and seven complementation groups, A-G, have been identified. Homologs of human excision repair genes ERCC1, XPDC/ERCC2, and XPAC have been identified in the yeast Saccharomyces cerevisiae. Since no homolog of human XPBC/ERCC3 existed among the known yeast genes, we cloned the yeast homolog by using XPBC cDNA as a hybridization probe. The yeast homolog, RAD25 (SSL2), encodes a protein of 843 amino acids (M(r) 95,356). The RAD25 (SSL2)- and XPBC-encoded proteins share 55% identical and 72% conserved amino acid residues, and the two proteins resemble one another in containing the conserved DNA helicase sequence motifs. A nonsense mutation at codon 799 that deletes the 45 C-terminal amino acid residues in RAD25 (SSL2) confers UV sensitivity. This mutation shows epistasis with genes in the excision repair group, whereas a synergistic increase in UV sensitivity occurs when it is combined with mutations in genes in other DNA repair pathways, indicating that RAD25 (SSL2) functions in excision repair but not in other repair pathways. We also show that RAD25 (SSL2) is an essential gene. A mutation of the Lys392 residue to arginine in the conserved Walker type A nucleotide-binding motif is lethal, suggesting an essential role of the putative RAD25 (SSL2) ATPase/DNA helicase activity in viability.
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PMID:RAD25 (SSL2), the yeast homolog of the human xeroderma pigmentosum group B DNA repair gene, is essential for viability. 133 9

A hamster DNA repair gene has been isolated by cosmid rescue after two rounds of transfection of an immortalized xeroderma pigmentosum (XP) complementation group D cell line with neomycin-resistance gene (neo)-tagged normal hamster DNA and selection with G418 and ultraviolet irradiation. The functional length of the sequence has been defined as 11.5 kilobase pairs by measurement of the region of overlap between two hamster DNA-containing cosmids, cloned by selection for the integrated neo gene, that are able to confer an increase in resistance to ultraviolet irradiation on two XP-D cell line but not on an XP-A line. Detailed molecular characterization of the hamster repair gene has revealed no obvious similarities to two human excision repair genes (ERCC1 and ERCC2) that correct repair-defective hamster cells but have no effect on XP cells. Hybridization analyses of normal human and XP cell genomic DNAs and mRNAs, using a cosmid-clone probe from which repeated sequences have been removed, show that homologues are present and expressed in all cases.
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PMID:Molecular cloning and characterization of a mammalian excision repair gene that partially restores UV resistance to xeroderma pigmentosum complementation group D cells. 278 May 57

This review describes the evolution of research into the genetic basis of how different organisms use the process of excision repair to recognize and remove lesions from their cellular DNA. One particular aspect of excision repair, DNA incision, and how it is controlled at the genetic level in bacteriophage, bacteria, S. cerevisae, D. melanogaster, rodent cells and humans is examined. In phage T4, DNA is incised by a DNA glycosylase-AP endonuclease that is coded for by the denV gene. In E. coli, the products of three genes, uvrA, uvrB and uvrC, are required to form the UVRABC excinuclease that cleaves DNA and releases a fragment 12-13 nucleotides long containing the site of damage. In S. cerevisiae, genes complementing five mutants of the RAD3 epistasis group, rad1, rad2, rad3, rad4 and rad10 have been cloned and analyzed. Rodent cells sensitive to a variety of mutagenic agents and deficient in excision repair are being used in molecular studies to identify and clone human repair genes (e.g. ERCC1) capable of complementing mammalian repair defects. Most studies of the human system, however, have been done with cells isolated from patients suffering from the repair defective, cancer-prone disorder, xeroderma pigmentosum, and these cells are now beginning to be characterized at the molecular level. Studies such as these that provide a greater understanding of the genetic basis of DNA repair should also offer new insights into other cellular processes, including genetic recombination, differentiation, mutagenesis, carcinogenesis and aging.
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PMID:The molecular genetics of the incision step in the DNA excision repair process. 290 Aug 58

Cell strains derived from patients having a hereditary disorder associated with defects in repair of DNA damage such as xeroderma pigmentosum and mutants isolated from established rodent cell lines provide the tools for genetic and biochemical analysis of DNA repair pathways in mammalian cells. Complementation studies using these cells have illustrated the genetic and biochemical complexity of these pathways. The precise nature of the genes and gene products involved in these mutants has not yet been resolved. Isolation of repair genes by recombinant DNA technology would open up new approaches to the elucidation of repair mechanisms in mammalian cells. Here we report the molecular cloning of a human repair gene (ERCC1) that complements the repair defect in a Chinese hamster ovary (CHO) mutant cell line.
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PMID:Molecular cloning of a human DNA repair gene. 646 28

Previously, we reported two DNA repair-defective siblings who did not belong to any complementation group of xeroderma pigmentosum (XP) or Cockayne syndrome (CS). By surveying other photosensitive patients whose fibroblasts showed similar biochemical phenotypes, we found another nonconsanguineous Japanese patient belonging to the same complementation group as our previous cases. Postreplication repair of the cells derived from these patients was normal, indicating that they cannot be classified as XP variant. Neither transfection nor microinjection of the cells with the human DNA repair gene ERCC1, which is known not to correct any complementation groups of XP or CS, failed to correct the defect of these cells, indicating that they do not belong to the rodent complementation group 1. However, the defect in recovery of RNA synthesis (RRS) after UV irradiation was restored by microinjection of HeLa cell extract. Although clinical manifestations of these patients--such as acute sunburn, dryness, freckling, pigmentation anomalies on sun-exposed skin, and teleangiectasia without neurological abnormalities or tumors--are similar to a mild XP phenotype, cellular characteristics such as UV sensitivity and defective RRS after UV irradiation with normal unscheduled DNA synthesis (UDS) are reminiscent of CS. On the basis of these results, we propose that these patients be included under a general category designated "UV-sensitive" (UVs) syndrome.
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PMID:UVs syndrome, a new general category of photosensitive disorder with defective DNA repair, is distinct from xeroderma pigmentosum variant and rodent complementation group I. 776 48

The nucleotide excision repair (NER) protein ERCC1 is part of a functional complex, which harbors in addition the repair correcting activities of ERCC4, ERCC11 and human XPF. ERCC1 is not associated with a defect in any of the known human NER disorders: xeroderma pigmentosum, Cockayne's syndrome or trichothiodystrophy. Here we report the partial purification and characterization of the ERCC1 complex. Immunoprecipitation studies tentatively identified a subunit in the complex with an apparent MW of approximately 120 kDa. The complex has affinity for DNA, but no clear preference for ss, ds or UV-damaged DNA substrates. The size of the entire complex determined by non-denaturing gradient gels (approximately 280 kDa) is considerably larger than previously found using size separation on glycerol gradients (approximately 120 kDa). Stable associations of the ERCC1 complex with other known repair factors (XPA, XPC, XPG and TFIIH complex) could not be detected.
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PMID:Partial characterization of the DNA repair protein complex, containing the ERCC1, ERCC4, ERCC11 and XPF correcting activities. 759 55

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 xeroderma pigmentosum complementation group A (XP-A) protein, XPA, has recently been expressed in Escherichia coli in a soluble and fully functional form. An affinity column was prepared by linking the XPA protein to a solid support. When HeLa cell-free extract capable of excision repair was applied to the column, > 99.9% of the proteins were in the flow-through. However, the flow-through fraction lacked excision activity. The activity was restored by adding the high salt (1 M KCl) eluate of the column to the flow-through fraction. The XPA protein-bound fraction was tested for specific proteins by an in vitro complementation assay with a panel of cell-free extracts from DNA repair-deficient human and rodent cell lines. The XPA-bound fraction complemented cell-free extracts of excision repair cross-complementing 1 (ERCC-1), ERCC-4 (XP-F), and XP-A mutants. We conclude that the XPA damage recognition protein makes a ternary complex with the ERCC1/ERCC4(XPF) heterodimer with a potential nuclease function.
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PMID:Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins. 819 75

The mammalian ERCC1-encoded polypeptide is required for nucleotide excision repair of damaged DNA and is homologous to Saccharomyces cerevisiae RAD10, which functions in repair and mitotic intrachromosomal recombination. Rodent cells representing repair complementation group 1 have nonfunctional ERCC1. We report that repair of UV-irradiated DNA can be reconstituted by combining rodent group 1 cell extracts with correcting protein from HeLa cells. Background repair was minimized by employing fractionated rodent cell extracts supplemented with human replication proteins RPA and PCNA. Group 1-correcting activity has a native molecular mass of 100 kDa and contains the 33 kDa ERCC1 polypeptide, as well as complementing activities for extracts from rodent group 4 and xeroderma pigmentosum group F (XP-F) cells. Extracts of group 1, group 4 or XP-F cells do not complement one another in vitro, although they complement extracts from other groups. The amount of ERCC1 detectable by immunoblotting is reduced in group 1, group 4 and XP-F extracts. Recombinant ERCC1 from Escherichia coli only weakly corrected the group 1 defect. The data suggest that ERCC1 is part of a functional protein complex with group 4 and XP-F correcting activities. The latter two may be equivalent to one another and analogous to S. cerevisiae RAD1.
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PMID:Co-correction of the ERCC1, ERCC4 and xeroderma pigmentosum group F DNA repair defects in vitro. 825 90

Nucleotide excision repair (NER), one of the major cellular DNA repair systems, removes a wide range of lesions in a multi-enzyme reaction. In man, a NER defect due to a mutation in one of at least 11 distinct genes, can give rise to the inherited repair disorders xeroderma pigmentosum (XP), Cockayne's syndrome or PIBIDS, a photosensitive form of the brittle hair disease trichothiodystrophy. Laboratory-induced NER-deficient mutants of cultured rodent cells have been classified into 11 complementation groups (CGs). Some of these have been shown to correspond with human disorders. In cell-free extracts prepared from rodent CGs 1-5 and 11, but not in a mutant from CG6, we find an impaired repair of damage induced in plasmids by UV light and N-acetoxy-acetylaminofluorene. Complementation analysis in vitro of rodent CGs is accomplished by pairwise mixing of mutant extracts. The results show that mutants from groups 2, 3, 5 and XP-A can complement all other CGs tested. However, selective non-complementation in vitro was observed in mutual mixtures of groups 1, 4, 11 and XP-F, suggesting that the complementing activities involved somehow affect each other. Depletion of wild-type human extracts from ERCC1 protein using specific anti-ERCC1 antibodies concomitantly removed the correcting activities for groups 4, 11 and XP-F, but not those for the other CGs. Furthermore, we find that 33 kDa ERCC1 protein sediments as a high mol. wt species of approximately 120 kDa in a native glycerol gradient.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for a repair enzyme complex involving ERCC1 and complementing activities of ERCC4, ERCC11 and xeroderma pigmentosum group F. 825 91


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