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New cellular traits of Cockayne's syndrome (CS) associated with DNA precursor metabolism have been identified, namely, hypersensitivity to the toxicity of low concentrations of deoxyguanosine (dG) and abnormal changes in deoxyribonucleotide (dNTP) pools in response to dG or UV. dG treatment results in similar ribonucleotide pool changes in wild-type and CS cells, i.e., GTP levels increase at least twofold. However, the changes in the pool size of the purine deoxyribonucleotides are significantly different; in wild-type cells dATP and dGTP pools increase threefold, but remain unchanged in CS. The mechanism by which dG kills CS cells is not clear, but unlike the inherited purine nucleoside phosphorylase deficiency disease, the toxicity of dG is not due to the accumulation of dGTP and the consequent feedback inhibition of ribonucleotide reductase. UV induces different dNTP pool changes in CS and wild-type cells. In wild-type cells dTTP, dCTP, and dATP pools increase three- to fivefold within 4 h of irradiation, while the dGTP pool contracts. In CS cells, only the dGTP pool expands (four- to sixfold), while the other three contract. Each of these new phenotypic traits, together with UV sensitivity, is coordinately corrected in the complementing proliferating CSA x CSB hybrid cells.
Somat Cell Mol Genet 1992 Sep
PMID:Cockayne's syndrome fibroblasts are characterized by hypersensitivity to deoxyguanosine and abnormal DNA precursor pool metabolism in response to deoxyguanosine or ultraviolet light. 147 5

By comparing fibroblast strains derived from individuals exhibiting chromosome instability and/or mutagen hypersensitivity (Cockayne syndrome, ataxia telangiectasia, and Fanconi anemia) with strains derived from healthy donors, the fibroblast micronucleus assay has been established as a reproducible measure of the genotypic variation in spontaneous or mitomycin C (MMC)-induced chromosomal instability. The patient strains that were moderately or exquisitely sensitive to MMC, whereas the mildly sensitive strain (Cockayne syndrome) overlapped with the control range. The reproducibility of the assay was evaluated within and between experiments. Paired comparison analyses between duplicate cultures and between repeat experiments failed to show any significant differences between micronucleus frequencies within strains, whereas a significant differences in the spontaneous micronucleus frequencies between strains was observed. In addition to its value as a test system for genotoxins, the fibroblast micronucleus assay may be useful for investigating genetically determined hypersensitivity to mutagens, elevated spontaneous chromosomal breakage, and chromosome segregation errors.
Environ Mol Mutagen 1988
PMID:Micronucleus assay in human fibroblasts: a measure of spontaneous chromosomal instability and mutagen hypersensitivity. 313 7

Pretibial epidermolysis bullosa (PEB) is a rare variant of dominant dystrophic EB (DDEB) in which recurrent blistering with scarring predominantly involves the pretibial skin. Although blistering appears to be localized clinically, electron microscopy of the dermalepidermal junction in patients with PEB reveals anchoring fibril abnormalities that are not restricted to the predilection sites. Furthermore, PEB cannot be distinguished from the generalized (Cockayne-Touraine and Pasini) types of DDEB on the basis of anchoring fibril morphology alone. The generalized forms of DDEB have been linked to the type VII collagen gene (COL7A1) on chromosome 3p21. In this study, we sought to test the hypothesis that mutations underlying PEB also reside in COL7A1. We initiated mutational analysis in COL7A1 in a large five-generation PEB family of Taiwanese descent. We identified a G-to-T transversion at nt position 7867, which results in a glycine-to-cysteine substitution (G2623C) in exon 105. This mutation was confirmed in affected family members using the loss of a SmaI restriction site, and when used for linkage analysis, together with an intragenic PvuII polymorphism and several flanking markers, resulted in a LOD score of Z = 3.61 at theta = 0 in this family. This is the first demonstration of genetic linkage and mutation analysis in PEB, and illustrates that the Cockayne-Touraine, Pasini, and now the pretibial clinical variants of DDEB are allelic, resulting from different glycine substitution mutations in the type VII collagen gene.
Hum Mol Genet 1995 Sep
PMID:Pretibial epidermolysis bullosa: genetic linkage to COL7A1 and identification of a glycine-to-cysteine substitution in the triple-helical domain of type VII collagen. 854 42

The nucleotide excision repair (NER) pathway is thought to consist of two subpathways: transcription-coupled repair, limited to the transcribed strand of active genes, and global genome repair for nontranscribed DNA strands. Recently we cloned the RAD26 gene, the Saccharomyces cerevisiae homolog of human CSB/ERCC6, a gene involved in transcription-coupled repair and the disorder Cockayne syndrome. This paper describes the analysis of yeast double mutants selectively affected in each NER subpathway. Although rad26 disruption mutants are defective in transcription-coupled repair, they are not UV sensitive. However, double mutants of RAD26 with the global genome repair determinants RAD7 and RAD16 appeared more UV sensitive than the single rad7 or rad16 mutants but not as sensitive as completely NER-deficient mutants. These findings unmask a role of RAD26 and transcription-coupled repair in UV survival, indicate that transcription-coupled repair and global genome repair are partially overlapping, and provide evidence for a residual NER modality in the double mutants. Analysis of dimer removal from the active RPB2 gene in the rad7/16 rad26 double mutants revealed (i) a contribution of the global genome repair factors Rad7p and Rad16p to repair of the transcribed strand, confirming the partial overlap between both NER subpathways, and (ii) residual repair specifically of the transcribed strand. To investigate the transcription dependence of this repair activity, strand-specific repair of the inducible GAL7 gene was investigated. The template strand of this gene was repaired only under induced conditions, pointing to a role for transcription in the residual repair in the double mutants and suggesting that transcription-coupled repair can to some extent operate independently from Rad26p. Our findings also indicate locus heterogeneity for the dependence of transcription-coupled repair on RAD26.
Mol Cell Biol 1996 Feb
PMID:Double mutants of Saccharomyces cerevisiae with alterations in global genome and transcription-coupled repair. 855 76

Two of the hallmarks of Cockayne's syndrome (CS) are the hypersensitivity of cells to UV light and the lack of recovery of the ability to synthesize RNA following exposure of cells to UV light, in spite of the normal repair capacity at the overall genome level. The prolonged repressed RNA synthesis has been attributed to a defect in transcription-coupled repair, resulting in slow removal of DNA lesions from the transcribed strand of active genes. This model predicts that the sensitivity of CS cells to another DNA-damaging agent, i.e., the UV-mimetic agent N-acetoxy-2-acetylaminofluorene (NA-AAF), should also be associated with a lack of resumption of RNA synthesis and defective transcription-coupled repair of NA-AAF-induced DNA adducts. We tested this by measuring the rate of excision of DNA adducts in the adenosine deaminase gene of primary normal human fibroblasts and two CS (complementation group A and B) fibroblast strains. High-performance liquid chromatography analysis of DNA adducts revealed that N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF) was the main adduct induced by NA-AAF in both normal and CS cells. No differences were found between normal and CS cells with respect to induction of this lesion either at the level of the genome overall or at the gene level. Moreover, repair of dG-C8-AF in the active adenosine deaminase gene occurred at similar rates and without strand specificity in normal and CS cells, indicating that transcription-coupled repair does not contribute significantly to repair of dG-C8-AF in active genes. Yet CS cells are threefold more sensitive to NA-AAF than are normal cells and are unable to recover the ability to synthesize RNA. Our data rule out defective transcription-coupled repair as the cause of the increased sensitivity of CS cells to DNA-damaging agents and suggest that the cellular sensitivity and the prolonged repressed RNA synthesis are primarily due to a transcription defect. We hypothesize that upon treatment of cells with either UV or NA-AAF, the basal transcription factor TFIIH becomes involved in nucleotide excision repair and that the CS gene products are involved in the conversion of TFIIH back to the transcription function. In this view, the CS proteins act as repair-transcription uncoupling factors. If the uncoupling process is defective, RNA synthesis will stay repressed, causing cellular sensitivity. Since transcription is essential for transcription-coupled repair, the CS defect will affect those lesions whose repair is predominantly transcription coupled, i.e., UV-induced cyclobutane pyrimidine dimers.
Mol Cell Biol 1996 Aug
PMID:The sensitivity of Cockayne's syndrome cells to DNA-damaging agents is not due to defective transcription-coupled repair of active genes. 875 44

Rodent UV-sensitive mutant cell lines of complementation groups 6 and 8 are the genetic counterparts of human Cockayne syndrome CS-B and CS-A, respectively. The original mutant in this group, UV61, was described as defective in cyclobutane pyrimidine dimer removal after high doses of UV. We have examined the responses of several cell lines from group 6 to low doses of UV irradiation, and find that these mutants have wild-type capacity for DNA repair as indicated by incision, cyclobutane pyrimidine dimer, and (6-4) photoproduct removal. ERCC6, the product of the gene defective in CS-B and group 6 mutants, is implicated in the regulation of repair of actively transcribed genes in Cockayne syndrome; however, this protein clearly is not required for the processing of low levels of damage in CHO cells, which occurs remarkably efficiently, 40-50% of dimers being removed in both wild-type and group 6 mutants in 5 hours following 0.1 Jm(-2) of UV. The group 8 mutant cell line US31, on the other hand, is very deficient in repair of UV damage, showing a more extreme phenotype than is seen in the corresponding human syndrome CS-A. In both complementation groups, expression of mutations in a gene involved in regulation of DNA repair takes very different forms in human and rodent cells.
Environ Mol Mutagen 1997
PMID:UV-sensitive rodent mutant cell lines of complementation groups 6 and 8 differ phenotypically from their human counterparts. 911 67

Cockayne's syndrome (CS) is a disease characterized by developmental and growth defects, sunlight sensitivity, and a defect in transcription-coupled nucleotide excision repair. The two principle proteins involved in CS, CSA and CSB/ERCC6, have been hypothesized to bind RNA polymerase II (Pol II) and link transcription to DNA repair. We have tested CSA and CSB in assays designed to determine their role in transcription-coupled repair. Using a unique oligo(dC)-tailed DNA template, we provide biochemical evidence that CSB/ERCC6 interacts with Pol II molecules engaged in ternary complexes containing DNA and nascent RNA. CSB is a DNA-activated ATPase, and hydrolysis of the ATP beta-gamma phosphoanhydride bond is required for the formation of a stable Pol II-CSB-DNA-RNA complex. Unlike CSB, CSA does not directly bind Pol II.
Mol Cell Biol 1997 Dec
PMID:Recruitment of the putative transcription-repair coupling factor CSB/ERCC6 to RNA polymerase II elongation complexes. 937 11

Nucleotide excision repair (NER) is a process required to remove DNA damage inflicted upon our skin by the short-wave bands of natural sunlight. Defective NER may result in a high risk of UV-induced skin tumors, since it occurs in patients with the inherited disorder xeroderma pigmentosum (XP). However, Cockayne's syndrome (CS) and PIBIDS (a photosensitive form of trichothiodystrophy) are also disorders with defective NER, but show no evidence of an elevated risk of cancer. In addition, many of CS and PIBIDS symptoms are difficult to explain on the basis of an NER defect only. Recent new insights into the molecular mechanisms of NER have shown additional involvements of many NER enzymes in other cellular processes. These multiple functions are likely to be the basis of the complex symptomatology of XP, CS and PIBIDS. Specific gene-targeted mouse models will probably help to solve these intricacies.
Cytokines Mol Ther 1996 Jun
PMID:Multiple involvement of nucleotide excision repair enzymes: clinical manifestations of molecular intricacies. 938 96

Trichothiodistrophy (TTD), xeroderma pigmentosum (XP), and Cockayne's syndrome (CS) are three distinct human diseases with sensitivity to ultraviolet (UV) radiation affected by mutations in genes involved in nucleotide excision repair (NER). Among the many responses of human cells to UV irradiation, both nuclear accumulation of p53, a tumor suppressor protein, and alterations in cell-cycle checkpoints play crucial roles. The purpose of this study was to define the signals transmitted after UV-C-induced DNA damage, which activates p53 accumulation in TTD/XP-D fibroblasts, and compare this with XP-D cell lines that carry different mutations in the same gene, XPD. Our results showed that p53 was rapidly induced in the nuclei of TTD/XP-D and XP-D fibroblasts in a dose-dependent manner after UV-C irradiation, as seen in XP-A and CS-A fibroblasts, much lower doses being required for the protein accumulation than in normal human fibroblasts, XP variant cells, and XP-C cells. The kinetics of accumulation of p53 and two effector proteins involved in cell-cycle arrest, WAF1 and GADD45, were also directly related to the repair potential of the cells, as in normal human fibroblasts their levels declined after 24 h, the time required for repair of UV-induced lesions, whereas NER-deficient TTD/XP-D cells showed p53, WAF1, and GADD45 accumulation for over 72 h after irradiation. Our results indicate that p53 accumulation followed by transcriptional activation of genes implicated in growth arrest is triggered in TTD/XP-D cells by the persistence of cyclobutane pyrimidine dimers, which are known to block transcription, on the transcribed strands of active genes.
Mol Carcinog 1997 Dec
PMID:Prolonged p53 protein accumulation in trichothiodystrophy fibroblasts dependent on unrepaired pyrimidine dimers on the transcribed strands of cellular genes. 943 78

The Saccharomyces cerevisiae transcription factor IIH (TFIIH) is essential both for transcription by RNA polymerase II (RNAP II) and for nucleotide excision repair (NER) of damaged DNA. We have established cell extracts which support RNAP II transcription from the yeast CYC1 promoter or NER of transcriptionally silent damaged DNA on independent plasmid templates and substrates. When plasmid templates and substrates for both processes are simultaneously incubated with these extracts, transcription is significantly inhibited. This inhibition is strictly dependent on active NER and can be complemented with purified holo-TFIIH. These results suggest that in the presence of active NER, TFIIH is preferentially mobilized from the basal transcription machinery for use in NER. Inhibition of transcription in the presence of active NER requires the RAD26 gene, the yeast homolog of the human Cockayne syndrome group B gene (CSB).
Mol Cell Biol 1998 May
PMID:Yeast RNA polymerase II transcription in vitro is inhibited in the presence of nucleotide excision repair: complementation of inhibition by Holo-TFIIH and requirement for RAD26. 956 86


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