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 capacity of a variety of human fibroblasts to incise DNA following exposure to far ultraviolet-light is determined from the rate of single-strand DNA break accumulation in the presence of DNA synthesis inhibitors. We have quantitated incision, one of the early steps in the UV excision repair pathway, in cells form normal, xeroderma pigmentosum groups C, D, G, H and variant individuals, and in the parents of one XPA patient. On the basis of the estimated initial rates of incision the different XP cells examined in this work can be ranked as follows: XP variant much greater than XPH greater than XPH greater than XPD greater than XPC greater than XPG greater than XPA. In each cell strain breaks accumulate immediately after irradiation over a range of 0.5-20 Jm-2 with the exception of the XPC strain examined, where there is an initial delay of 15 min. The rate of incision in XPA heterozygote cells is roughly half that of normal fibroblasts. Analysis of the kinetics of break accumulation over short intervals after irradiation permits estimation of the apparent enzymatic parameters, Km and Vmax, for the incision step. The approximate values of Km and Vmax for normal and XP variant are similar while for the heterozygotes of an XPA individual Km values are normal (around 1 Jm-2), but there is only half the amount of normal enzyme activity. XPD and H cells express low levels of active enzyme, between 5 and 15% of that of the normal, but while the Km of XPH is very similar to that of normal cells, that of two XPD strains examined is between 2- and 3-fold higher.
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PMID:Kinetic analysis of UV-induced incision discriminates between fibroblasts from different xeroderma pigmentosum complementation groups, XPA heterozygotes and normal individuals. 334 9

Chromosome and blood marker studies were performed in the families of 4 patients in which the association of 2 rare recessive Mendelian disorders, xeroderma pigmentosum (XP-D) and trichothiodystrophy (TTD), was present. Blood genotypes did not indicate any linkage with the pathologic condition, nor any segregation anomaly. Cytogenetic analysis using high-resolution banding techniques showed a normal karyotype both in the heterozygous and in the homozygous individuals. These findings lead us to exclude a cytologically detectable chromosome rearrangement, such as a microdeletion, as a possible cause of the association of XP-D and TTD in our patients.
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PMID:Chromosome and blood marker studies in families of patients affected by xeroderma pigmentosum and trichothiodystrophy. 339 68

Several lines of evidence indicate that eukaryotic DNA is arranged in highly supercoiled domains or loops, and that the repeating loops are constrained by attachment to a nuclear skeletal structure termed the nuclear matrix. Active genes are transcribed at the nuclear matrix and during replication the loops are reeled through fixed matrix-associated replication complexes. We have investigated whether the repair of DNA damage also occurs in the nuclear matrix compartment. Biochemical analysis of confluent normal human fibroblasts, ultraviolet (u.v.)-irradiated with 30 J m-2 and post-u.v. incubated in the presence of hydroxyurea, did not show any evidence for the occurrence of repair synthesis at the nuclear matrix either 30 min or 13 h after irradiation. Autoradiographic visualization of repair events in single DNA halo-matrix structures confirmed the biochemical observations. At a biologically more relevant dose of 5 J m-2 repair synthesis seems to initiate at the nuclear matrix, although only part of the total repair could be localized there. In u.v.-irradiated (30 J m-2) normal human fibroblasts post-u.v. incubated in the presence of hydroxyurea and arabinosylcytosine for 2 h, multiple single-stranded regions are generated in a DNA loop as a result of the inhibition of the excision repair process. Different biochemical approaches revealed that most of the single-stranded regions are clustered, indicating that the repair process itself is non-random or that domains in the chromatin are repaired at different rates. Preferential repair of certain domains in the chromatin was shown to occur in xeroderma pigmentosum cells of complementation group C (XP-C). In XP-C cells these domains are localized near the attachment sites of DNA loops at the nuclear matrix. In contrast, xeroderma pigmentosum cells of complementation group D as well as Syrian hamster embryonic cells with limited excision-repair capacities, revealed a random distribution of repair events in DNA loops. The preferential repair of matrix-associated DNA in XP-C cells may be related partly to repair of transcriptionally active DNA and this may account for the ability of XP-C cells, in contrast to XP-D cells, to recover u.v.-inhibited synthesis of DNA and RNA.
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PMID:The localization of ultraviolet-induced excision repair in the nucleus and the distribution of repair events in higher order chromatin loops in mammalian cells. 347 64

Two intraspecific human cell hybrids, HD2 and HD1A, produced from fusion between HeLa cells and xeroderma pigmentosum fibroblasts, express XPD-like rates of excision repair and hypersensitivity to UV-radiation. In the present paper we describe unusual patterns of UV-induced mutation in both cell lines. Though HD2 very closely resembles XPD both phenotypically and genetically, in UV-dose response it is hypomutable at the loci for ouabain and diphtheria toxin resistance. At equitoxic dose, however, it shows normal mutability, HD1A, by contrast, is hypermutable as a function either of UV dose or in terms of equitoxicity for these genes. HD1A's mutator phenotype is a dominant characteristic and is not associated with grossly abnormal DNA precursor pool imbalance. The possibility remains that DNA polymerase infidelity underlies its hypermutability.
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PMID:Abnormal mutation frequencies in human repair-defective hybrid cell lines. 362 40

Hybrids formed between HeLa cells and fibroblasts from xeroderma pigmentosum group D show either HeLa sensitivity or XPD-like hypersensitivity to u.v. radiation and corresponding high or low excision repair capability. Hybrids with low repair are presumed to have lost, via chromosome segregation, the HeLa wild type D alleles. In this paper we analyse the u.v. sensitivity and excision repair capability of another hybrid, HD1A, derived spontaneously from the normally sensitive hybrid HD1. While HD1A closely resembles the XPD phenotype in terms of u.v. sensitivity and excision repair it differs from XPD because of its ability to reactivate u.v.-irradiated adenovirus 2 to an extent similar to that of its HeLa parent. This capacity functionally dissociates excision repair of chromatin-based damage from damage in a viral environment. Moreover, on the basis of complementation studies the excision repair of genomic damage by HD1A is subtly different from that of a true XPD-like hybrid, HD2. The data are discussed in terms of a second change in the defective D allele of the HD1A cell.
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PMID:Analysis of DNA repair in XP-HeLa hybrids; lack of correlation between excision repair of u.v. damage and adenovirus reactivation in an XP(D)-like cell line. 375 74

Fusion between HeLa and fibroblasts from complementation group D xeroderma pigmentosum (XPD) followed by challenge with small doses of ultraviolet light (u.v.) results in the production of hybrid cells expressing either HeLa (HD1) or XPD-like (HD2) sensitivity to u.v. and related repair capacity. Assays used included unscheduled DNA synthesis (UDS), DNA break accumulation in the presence of inhibitors of DNA repair synthesis and host cell reactivation of irradiated adenovirus. Complementation assay in heterokaryons reveals limited ability of HD2 to restore UDS in XPD nuclei. We believe this complementation is more apparent than real since proliferating hybrids of HD2 and XPD parentage are without exception u.v.-sensitive and express limited excision repair. On the other hand hybrids between HD2 and XPC, XPE or XPF fibroblasts show true complementation resulting in a return to normal u.v. sensitivity and elevated repair ability.
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PMID:Xeroderma pigmentosum D-HeLa hybrids with low and high ultraviolet sensitivity associated with normal and diminished DNA repair ability, respectively. 406 82

We have examined the fate of the asymmetric chromosomal distribution of DNA adducts generated by the chemical carcinogen r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydro-benzo[a]pyrene (BPDE). Treatment of mouse embryo cells with BPDE results in 3.5 times more binding to the linker DNA regions between nucleosome cores than to the nucleosome core DNA itself, but 24 h post-treatment incubation of these cells leads to a loss of this non-random binding. A similar result was obtained when post-treatment incubation was carried out in the presence of hydroxyurea indicating that factors other than DNA replication are responsible for this changes in adduct distribution. However in the case of excision repair deficient xeroderma pigmentosum (XP12/BE) cells the non-random adduct distribution was stable over a period of 48 h, whereas with excision repair proficient XP variant (XP4/BE cells, loss of preferential binding did occur. There results indicate that the loss of non-random nucleosomal DNA modification with time can be accounted for by the preferential removal of adducts from micrococcal nuclease sensitive linker DNA and further, demonstrates that in certain cells at least, the relative position of nucleosome core structures on DNA remains unchanged over a period of at least 48 h.
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PMID:Mechanism for the loss of preferential benzo [a] pyrene binding to the linker DNA of chromatin. 628 89

Human fibroblasts and HeLa cells contain two major DNA-binding activities for superhelical DNA, which can be separated by phosphocellulose chromatography. The DNA-binding activity which elutes first from the column coelutes with and is probably identical to a single-stranded-DNA-binding activity. The second activity has been characterized previously. It binds preferentially to super-helical DNA containing DNA damage, but does not bind to single-stranded DNA. Five cell lines derived from patients with the repair-deficiency syndrome xeroderma pigmentosum (XP) were analyzed for the presence of these binding activities. Four of the cell lines were from the A-complementation group and one was from the D-complementation group of XP. The binding activity with preference for damaged DNA was present in all cell lines. The single-stranded-DNA-binding activity was present in the XP-D cell line but was absent or reduced in all of the four XP-A cell lines tested.
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PMID:Cell lines from xeroderma pigmentosum complementation group A lack a single-stranded-DNA-binding activity. 668 57

Xeroderma pigmentosum of groups A, C and D shows complementation differing in kinetics, dependence on the dose of wild-type alleles and dependence on protein synthesis. Such differences suggest that XP-A, -C and -D carry mutations at different loci. The product of the first of these loci (factor A) is present in significant excess in normal fibroblasts, seems to turn over rapidly and may be a dimer or higher polymer. The products of the other two loci (factors C and D) do not seem to be present in significant excess in the cytoplasm of normal fibroblasts, but factor C may accumulate abnormally in XP-D. Factors C and D turn over slowly (D more than C) and they do not move freely from the cell nucleus. Factors A and C, at least, seem to act directly and not via gene regulation.
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PMID:Differences in patterns of complementation of the more common groups of xeroderma pigmentosum: possible implications. 711 46

The regulation of nucleotide excision repair and base excision repair by normal and repair deficient human cells was determined. Synchronous cultures of WI-38 normal diploid fibroblasts and Xeroderma pigmentosum fibroblasts (complementation group D) (XP-D) were used to investigate whether DNA repair pathways were modulated during the cell cycle. Two criteria were used: (1) unscheduled DNA synthesis (UDS) in the presence of hydroxyurea (HU) after exposure to UV light or after exposure to N-acetoxy-acetylaminofluorene (N-AcO-AAF) to quantitate nucleotide excision repair or UDS after exposure to methylethane sulfonate (MMS) to measure base excision repair; (2) repair replication into parental DNA in the absence of HU after exposure to UV light. Nucleotide excision repair after UV irradiation was induced in WI-38 fibroblasts during the cell cycle reaching a maximum in cultures exposed 14--15 h after cell stimulation. Similar results were observed after exposure to N-AcO-AAF. DNA repair was increased 2--4-fold after UV exposure and was increased 3-fold after N-AcO-AAF exposure. In either instance nucleotide excision repair was sequentially stimulated prior to the enhancement of base excision repair which was stimulated prior to the induction of DNA replication. In contrast XP-D failed to induce nucleotide excision repair after UV irradiation at any interval in the cell cycle. However, base excision repair and DNA replication were stimulated comparable to that enhancement observed in WI-38 cells. The distinctive induction of nucleotide excision repair and base excision repair prior to the onset of DNA replication suggests that separate DNA repair complexes may be formed during the eucaryotic cell cycle.
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PMID:Cell cycle regulation of DNA repair in normal and repair deficient human cells. 724 49


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