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 ability of an XPA minigene construct to complement the DNA repair defect in xeroderma pigmentosum group A (XP-A) cells was demonstrated. XP-A cells (XP12BE-SV) were stably transformed with an XPA minigene linked to a neomycin resistance (neor) expression cassette. The G418-resistant clone XAN1 was isolated and its DNA repair phenotype compared with XP12BE-SV cells transformed with a cosmid containing a human chromosome 8 gene and a neo(r) cassette and selected for G418 resistance (2-0-A2), DNA repair-normal human fibroblasts and untransfected XP12BE-SV cells. Colony forming ability after UV-irradiated reactivation of a UV-irradiated chloramphenicol acetyltransferase (CAT) expression vector and UV-induced mutagenesis in a supF tRNA shuttle vector (pSP189) were all restored to normal levels in XAN1 cells. In addition, mutation spectra in the supF gene of pSP189 after replication in all four cell lines were compiled at low (100 J/m2) and high (1000 J/m2) UV doses. The majority of mutations were point mutations and these were predominately G:C-->A:T transitions regardless of dose for all cell lines. Dose-dependent differences were observed in the positions of mutation hot spots in pSP189 mutation spectra after replication in all four cell lines. Mutation spectra for XAN1 and GM0637 cells had only minor differences. An increase in the proportion of transversions was observed only in plasmids irradiated with a low UV dose and replicated in XAN1 cells. 2-0-A2 cells were reported to have partial restoration of DNA repair that was later suggested to be caused by a reversion. 2-0-A2 cells were nearly identical to XP12BE-SV cells in all aspects investigated, indicating that transformation to neor had no effect on DNA repair in these cells.
Carcinogenesis 1996 Sep
PMID:Stable transformation of xeroderma pigmentosum group A cells with an XPA minigene restores normal DNA repair and mutagenesis of UV-treated plasmids. 882 13

Roberts syndrome (RS) is a rare, recessively inherited disorder characterized by growth retardation, limb reductions and craniofacial deformities. Cells from a subset of afflicted individuals, termed RS+, display unusual separation or puffing of the heterochromatic regions of their chromosomes and are hypersensitive to several DNA-damaging agents including mitomycin C (MMC) and cisplatin, both of which can induce interstrand crosslinks in DNA. For this reason, we have investigated the ability of RS+ fibroblasts to repair cisplatin-induced DNA lesions using adenoviris as a probe. Host cell reactivation of cisplatin-treated adenovirus (Ad) was significantly reduced in nucleotide excision repair (NER)-deficient xeroderma pigmentosum (XP) cells but was normal in the two RS+ fibroblast strains and the Fanconi's anemia (FA)fibroblast strain tested. The capacity of cisplatin-treated cells for Ad DNA synthesis was reduced in XP and FA cells compared to normal human cells, but was not reduced in RS+ cells. These results indicate that the hypersensitivity of RS+ cells to cisplatin is not due to a deficiency in NER nor due to a deficiency in the pathway which leads to cisplatin hypersensitivity in FA cells. It is possible that the abnormal heterochromatin organisation of RS+ cells selectively renders the heterochromatic regions of the genome more susceptible to mutagen damage and/or less available for repair.
Somat Cell Mol Genet 1996 Sep
PMID:Roberts syndrome fibroblasts showing cisplatin hypersensitivity have normal host cell reactivation of cisplatin-treated adenovirus and normal capacity of cisplatin-treated cells for adenovirus DNA synthesis. 903 48

We have examined mechanisms of recombination in mammalian cells infected with herpes simplex virus type 1 (HSV-1). Amplification of plasmids containing a viral origin of replication, oriS, in cells superinfected with HSV-1 revealed that linear DNA could be efficiently converted to templates for replication. Two distinct pathways were observed: imprecise end joining and nonconservative homologous recombination. We noted that direct repeats of the viral a sequence promoted efficient nonconservative homologous recombination in BHK cells as well as human repair-proficient 1BR.3N cells and xeroderma pigmentosum group F (XP-F) cells. The reaction gave rise to functional a sequences supporting the formation of defective viruses. It did not seem to proceed by single-strand annealing since it occurred in the absence of XPF/ERCC4, the mammalian homolog of the Rad1 endonuclease from Saccharomyces cerevisiae. In contrast, direct repeats of a 161-bp nonviral sequence did not take part in nonconservative homologous recombination in XP-F cells. Our results suggest that homologous recombination may be involved in the circularization of viral genomes. Furthermore, they demonstrate that amplification of recombination products supported by HSV-1 allows a direct examination of pathways for double-strand-break repair in human cells.
J Virol 1997 Sep
PMID:Direct repeats of the herpes simplex virus a sequence promote nonconservative homologous recombination that is not dependent on XPF/ERCC4. 926 9

The hereditary disease Cockayne syndrome (CS) is a complex clinical syndrome characterized by arrested post-natal growth as well as neurological and other defects. The CSA and CSB genes are implicated in this disease. The clinical features of CS can also accompany the excision repair-defective hereditary disorder xeroderma pigmentosum (XP) from genetic complementation groups B, D or G. The XPB and XPD proteins are subunits of RNA polymerase II (RNAP II) transcription factor IIH (TFIIH). We show here that extracts of CS-A and CS-B cells, as well as those from XP-B/CS cells, support reduced levels of RNAP II transcription in vitro and that this feature is dependent on the state or quality of the template.
Nucleic Acids Res 1997 Sep 15
PMID:Reduced RNA polymerase II transcription in extracts of cockayne syndrome and xeroderma pigmentosum/Cockayne syndrome cells. 927 84

Because Japanese patients with complementation group A xeroderma pigmentosum (XP-A) show early skin cancer and severe neurologic dysfunction, their family members are greatly concerned about the risk of inherited disease. In contrast to western XP-A patients, almost all Japanese XP-A patients have two of the three mutations (nonsense mutation in exon 3, splicing mutation in intron 3, and non-sense mutation in exon 6), which are easily detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. This work was aimed to see whether PCR-RFLP analysis is useful for genetic counseling of XP patients' siblings who are potential carriers of an XP-A gene mutation. In two of the three case studies presented, the probands were homozygous for the splicing mutation in intron 3 of the gene. In their siblings receiving genetic counseling, no mutation was found in the mutation site in one case, and one splicing mutation was found in the second case. In the third case, the proband was a compound heterozygote for the splicing mutation and for an unidentified mutation; in her sibling, no mutation was found in either of these mutation sites. No mutation was found in the siblings' spouses. On the basis of these findings, we reassured the prospective parents that there was little probability of having XP children, but in the second and third cases, we told them that their apparently unaffected children might be carriers. Each couple subsequently had one unaffected child. Thus, PCR-RFLP analysis is useful for genetic counseling of family members of XP-A patients.
J Invest Dermatol 1997 Sep
PMID:PCR-RFLP analysis as an aid to genetic counseling of families of Japanese patients with group A xeroderma pigmentosum. 928 95

Proliferating cell nuclear antigen (PCNA) is a DNA polymerase accessory factor that is required for DNA replication during S phase of the cell cycle and for resynthesis during nucleotide excision repair of damaged DNA. PCNA binds to flap endonuclease 1 (FEN-1), a structure-specific endonuclease involved in DNA replication. Here we report the direct physical interaction of PCNA with xeroderma pigmentosum (XP) G, a structure-specific repair endonuclease that is homologous to FEN-1. We have identified a 28-amino acid region of human FEN-1 (residues 328-355) and a 29-amino acid region of human XPG (residues 981-1009) that contains the PCNA binding activity. These regions share key hydrophobic residues with the PCNA-binding domain of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1), and all three competed with one another for binding to PCNA. A conserved arginine in FEN-1 (Arg339) and XPG (Arg992) was found to be crucial for PCNA binding activity. R992A and R992E mutant forms of XPG failed to fully reconstitute nucleotide excision repair in an in vivo complementation assay. These results raise the possibility of a mechanistic linkage between excision and repair synthesis that is mediated by PCNA.
J Biol Chem 1997 Sep 26
PMID:The DNA repair endonuclease XPG binds to proliferating cell nuclear antigen (PCNA) and shares sequence elements with the PCNA-binding regions of FEN-1 and cyclin-dependent kinase inhibitor p21. 930 16

We have characterized six SV40-transformed xeroderma pigmentosum cell lines (XP20S and XP12BE derived from female donors, XP12RO-SV, XP3BR/12SV, XP4PA-SV and XP8CAC-SV from male donors) for their usability in HPRT mutation studies. All cell lines exhibit hypersensitivity, compared with MRC5CV1 cells, towards the cytotoxic action of UV-irradiation. They were all shown to be heteronuclear and hyperdiploid with pronounced variability in chromosome number. Fluorescence in situ hybridization (FISH) with an X-chromosomal library (X-chromosome painting) and BrdUrd-labelling of late-replicating X-chromosomes demonstrated the presence of variable numbers of X-chromosomes and additional X-chromosomal material and suggested the presence of more than one genetically active HPRT allele in the majority of cells of five cell lines. The cell line XP8CAC-SV (complementation group C) seemed to be most suitable for HPRT mutation studies due to its near-diploid karyotype with only one X-chromosome in the majority of cells. From this cell line, a clonal subline was established (XP8CAC-SV-C1) which revealed the same UV-hypersensitivity as the parental cell line and a near-diploid karyotype with one X-chromosome in 94% of the metaphases. Molecular analysis of the HPRT gene gave a normal PCR amplification pattern for all exons and the normal wild-type sequence of the cDNA. HPRT tests with (+)-anti-benzo[a]pyrene-7,8-diol-9,10-oxide [(+)-anti-BPDE] showed a reproducible, concentration related increase in mutant frequencies. Compared with results with MRC5CV1 cells, the obtained data indicate spontaneous and (+)-anti-BPDE-induced hypermutability of the XP line. XP8CAC-SV-C1 thus represents a permanent XP cell line with characteristic cellular XP features which is convenient for studying the influence of deficient excision repair on HPRT mutant frequencies and mutation spectra.
Mutagenesis 1997 Sep
PMID:Characterization of SV40-transformed xeroderma pigmentosum cell lines for their usability in HPRT mutation studies. 937 20

The simian parainfluenza virus 5 (SV5) V/P gene encodes two proteins: V and the phosphoprotein P. The V and P proteins are amino coterminal for 164 residues, but they have unique carboxyl termini. The unique carboxyl terminus of V contains seven cysteine residues, resembles a zinc finger, and binds two atoms of zinc. In a glutathione-S-transferase (GST)-fusion protein selection of cell lysate assay, the GST-V protein was found to interact with the 127-kDa subunit (DDB1) of the damage-specific DNA binding protein (DDB) [also known as UV-damaged DNA binding protein (UV-DDB), xeroderma pigmentosum group E binding factor (XPE-BF), and the hepatitis B virus X-associated protein 1 (XAP-1)]. A reciprocal GST-DDB1 fusion protein selection assay of SV5-infected cell lysates showed that DDB1 and V interact, and it was found that V and DDB1 could be coimmunoprecipitated from SV5-infected cells or from cells expressing V and DDB1 using the vaccinia virus T7 expression system. The interaction of V and DDB1 involves the carboxyl-terminal domain of V in that either deletion of the V carboxyl-terminal domain or substitution of the cysteine residues (C189, C193, C205, C207, C210, C214, and C217) in the zinc-binding domain with alanine was able to disrupt binding to DDB1. The V proteins of the mumps virus, human parainfluenza virus 2 (hPIV2), and measles virus have also been found to interact with DDB1 in GST-fusion protein selection assays using in vitro transcribed and translated DDB1.
Virology 1998 Sep 15
PMID:The V protein of the paramyxovirus SV5 interacts with damage-specific DNA binding protein. 974 Jul 90

Among the major responses of human cells to DNA damage is accumulation of the p53 tumor suppressor protein, which plays a crucial role as a cell-cycle checkpoint. We have already shown that this response is different in cells from the UV-hypersensitive human syndromes xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), which overlap with each other and arise from mutations in genes involved in nucleotide excision repair. In this paper we report that correction of the repair defect by retroviral-mediated transduction of the wild-type XPD gene in XP-D and TTD/XP-D untransformed primary fibroblasts leads to a normal p53 response in these cells. Thus, the complemented cells, like normal human fibroblasts, require higher UV doses (10 J/m2) for p53 induction than the parental repair-deficient XP-D or TTD/XP-D cells (both mapping at the XPD locus), which accumulate p53 protein at very low UV doses (2.5 and 5 J/m2). The p53 protein levels return to normal 24 h after irradiation when UV-induced lesions have been efficiently repaired by the restored NER activity. These data confirm our earlier results that p53 accumulation following UV treatment is directly related to the presence of unrepaired cyclobutane dimers on the transcribed strand of active genes.
Carcinogenesis 1998 Sep
PMID:Recovery of the normal p53 response after UV treatment in DNA repair-deficient fibroblasts by retroviral-mediated correction with the XPD gene. 977 45

Most gerontologists believe aging did not evolve, is accidental, and is unrelated to development. The opposite viewpoint is most likely correct. Genetic drift occurs in finite populations and leads to homozygosity in multiple-alleled traits. Episodic selection events will alter random drift towards homozygosity in alleles that increase fitness with respect to the selection event. Aging increases population turnover, which accelerates the benefit of genetic drift. This advantage of aging led to the evolution of aging systems (ASs). Periodic predation was the most prevalent episodic selection pressure in evolution. Effective defenses to predation that allow exceptionally long lifespans to evolve are shells, extreme intelligence, isolation, and flight. Without episodic predation, aging provides no advantage and aging systems will be deactivated to increase reproductive potential in unrestricted environments. The periodic advantage of aging led to the periodic evolution of aging systems. Newer aging systems co-opted and added to prior aging systems. Aging organisms should have one dominant, aging system that co-opts vestiges of earlier-evolved systems as well as vestiges of prior systems. In human evolution, aging systems chronologically emerged as follows: telomere shortening, mitochondrial aging, mutation accumulation, senescent gene expression (AS#4), targeted somatic tissue apoptotic-atrophy (AS#5), and female reproductive tissue apoptotic-atrophy (AS#6). During famine or drought, to avoid extinction, reproduction is curtailed and aging is slowed or somewhat reversed to postpone or reverse reproductive senescence. AS#4-AS#6 are gradual and reversible aging systems. The life-extending/rejuvenating effects of caloric restriction support the idea of aging reversibility. Development and aging are timed by the gradual loss of cytosine methylation in the genome. Methylated cytosines (5mC) inhibit gene transcription, and deoxyribonucleic acid (DNA) cleavage by restriction enzymes. Cleavage inhibition prevents apoptosis, which requires DNA fragmentation. Free radicals catalyze the demethylation of 5mC while antioxidants catalyze the remethylation of cytosine by altering the activity of DNA methyltransferases. Hormones act as either surrogate free radicals by stimulating the cyclic adenosine monophosphate (cAMP) pathway or as surrogate antioxidants through cyclic guanosine monophosphate (cGMP) pathway stimulation. Access to DNA containing 5mC inhibited developmental and aging genes and restriction sites is allowed by DNA helicase strand separation. Tightly wound DNA does not allow this access. The DNA helicase generates free radicals during strand separation; hormones either amplify or counteract this effect. Caloric restriction slows or reverses the aging process by increasing melatonin levels, which suppresses reproductive and free radical hormones, while increasing antioxidant hormone levels. Cell apoptosis during CR leads to somatic wasting and a release of DNA, which increases bioavailable cGMP. The rapid aging diseases of progeria, the three diseases: (xeroderma pigmentosum (XP), Cockayne syndrome(CS), and ataxia telangiectasia (AT)), and Werner's syndrome are related to or caused by defects in three separate DNA helicases. The rapid aging diseases caused by mitochondrial malfunctions mirror those seen in XP, CS, and AT. Comparing these diseases allows for assignment of the different symptoms of aging to their respective aging systems. Follicle-stimulating hormone (FSH) demethylates the genes of AS#4, luteinizing hormone (LH) of AS#5, and estrogen of AS#6 while cortisol may act cooperatively with FSH and LH, and 5-alpha dihydrotestosterone (DHT) with FSH in these role. The Werner's DNA helicase links timing of the age of puberty, menopause, and maximum lifespan in one mechanism. Telomerase is under hormonal control. Most cancers likely result from malfunctions in the programmed apoptosis of AS#5 and AS#6. The Hayflick limit is reached primarily through loss of cytosine methylation of genes that inhibit replication. Men suffer the diseases of AS#4 at a higher rate than women who suffer from AS#5 more often. Adult mammal cloning suggests aging-related cellular demethylation, and thus aging, is reversible. This theory suggests that the protective effect of smoking and ibuprofen for Alzheimer's disease is caused through LH suppression.
Med Hypotheses 1998 Sep
PMID:The evolution of aging: a new approach to an old problem of biology. 979 99


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