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)

Lymphoblastoid cell lines were established after transformation by Epstein-Barr virus of peripheral lymphocytes from xeroderma pigmentosum (XP) patients and normal donors. These lines expressed B-lymphocyte characteristics. Typical characteristics related to XP of these cell lines were not altered by transformation. Extracts of these cells catalyzed release of uracil (Ura) and 3-methyladenine (3MeAde) from Ura-containing DNA (Ura-DNA) and methylated DNA (Me-DNA), respectively. These two activities, Ura-DNA glycosylase and 3MeAde-DNA glycosylase, differed in heat stability. Extracts released Ura more rapidly and 3MeAde more slowly from a single-stranded DNA than from a double-stranded DNA. On incubation with reconstituted chromatins prepared from Ura-DNA and Me-DNA, respectively, with calf thymus chromosomal protein, cell extracts released all the Ura but about half the 3MeAde residues. The activity levels of these two enzymes of XP cells were similar to those of normal cells.
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PMID:DNA glycosylases of human lymphoblastoid cells. 23 57

The ability of gamma-irradiated adenovirus to produce viral structural antigens (Vag) was examined in several normal and Xeroderma pigmentosum (XP) fibroblast strains. The fibroblast cultures were infected with either irradiated or nonirradiated adenovirus and at 48 hours after infection, cells were examined for the presence of Vag using immunofluorescent staining. Survival of Vag synthesis for gamma-irradiated adenovirus had a D37 value of 47 +/- 4 x 10(4) rad following the infection of seven normal fibroblast strains. The survival of this viral function was found to be significantly less following infection of the XP strains. D37 values for Vag synthesis expressed as a percentage of that obtained on normal strains were obtained for a representative strain from each of the XP complementation groups: group A, 57 per cent; group B, 61 per cent; group C, 61 per cent, group D, 59 per cent; group E, 73 per cent; and variant, 75 per cent. These results indicate that XP cells have a reduced repair capacity for some type of gamma-ray-induced DNA damage.
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PMID:Decreased repair of gamma-irradiated adenovirus in Xeroderma pigmentosum fibroblasts. 23 70

The DNA extracted from xeroderma pigmentosum human fibroblasts previously irradiated with 12.5 J/m2 of UV light and pulse-labeled for 45 min with radioactive and (or) heavy precursors, was used to determine the structural characteristics of the replication fork. Density equilibrium centrifugation experiments showed that a fork moved 6 micrometer in 45 min and bypassed 3 pyrimidine dimers in both strands. The same length was covered in 15-20 min in control cells. The delay in irradiated cells was apparently due to pyrimidine dimers acting as temporary blocks to the fork movement. Evidence for this interpretation comes from kinetics of incorporation of [3H]thymidine into DNA, which show that the time necessary to attain a new stable level of DNA synthesis in irradiated cells is equivalent to that required for the replication fork to cover the interdimer distance in one strand. On the other hand, the action of S1 nuclease on DNA synthesized soon after irradiation gives rise to a bimodal distribution in neutral sucrose gradients, one peak corresponding to 43 X 10(6) daltons and the other to 3 X 10(6) daltons. These two DNA species are generated by the attack of the S1 nuclease on single-stranded regions associated with the replication fork. A possible explanation for these results is given by a model according to which there is a delayed bypass of the dimer in the leading strand and the appearance of gaps opposite pyrimidine dimers in the lagging strand, as a direct consequence of the discontinuous mode of DNA replication. In terms of the model, the DNA of 43 X 10(6) daltons corresponds to the leading strand, linked to the unreplicated branch of the forks, whereas the piece of 3 X 10(6) daltons is the intergap DNA coming from the lagging strand. Pulse and chase experiments reveal that the low molecular weight DNA grows in a pattern that suggests that more than one gap may be formed per replication fork.
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PMID:Structure of the replication fork in ultraviolet light-irradiated human cells. 23 82

Xeroderma pigmentosum (XP), Fanconi anaemia (FA), ataxia telangiectasia (AT) and Bloom disease (BS) are four rare autosomal recessive disorders in which there is defective DNA repair and/or chromosome instability and proneness to malignancy. Between 80 and 90% of patients with XP have a defect, demonstrable at cell level, of excision of DNA lesions induced by ultraviolet rays, while the remainder have a cellular error of post-replication repair. XP cells are also deficient in repairing DNA damage caused by a variety of chemical mutagens. There are at least five different complementation groups of the first, or classical, type of XP (A to D, etc.) Apparently group C patients, as well as those with defective post-replication repair, do not show the progressive neurological illness found in a proportion of the other patients. AT is heterogeneous clinically and genetically. Clinically it presents with a progressive neurological illness, progressive telangiectases and a developmental disorder of the thymus. AT is characterized by sensitivity to X-rays and AT cells are unable to repair gamma-ray-induced damage to bases in the DNA. It appears that in many cases of the disorder a chromosomally marked cellular clone is found. In BS the main defect, which results in growth retardation, sun-induced lesions of the face and susceptibility to infection, appears to be a slow DNA chain maturation during DNA synthesis. An increase of sister chromatid exchanges is characteristically seen in the chromosomes of cultured BS cells. In FA, in which there is progressive pancytopenia with eventual bone marrow exhaustion and a tendency to haemorrhage and infection, the cellular defect seems to consist of faulty removal of repair of cross-links in the DNA. In this condition, as in BS and AT, various structural chromosome changes are detected in cultured cells. Patients with XP develop skin cancers in early life and often maligant melanomas. In the other three disorders, in which an immune deficiency is often present, leukaemia and related proliferative disorders are a frequent cause of death while other malignancies also occur. There is some evidence that points to an increased risk of malignancy in heterozygotes who carry the FA and AT genes.
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PMID:DNA repair defects and chromosome instability disorders. 25 77

The rate and extent of disappearance of two DNA lesions (pyrimidine dimers and covalently bound acetylaminofluorene), both thought to be removed by the so-called wide-patch (approximately 100 nucleotides) repair process, were studied in a variety of cultured mammalian cells. With the exception of mouse cells, dimers were removed more rapidly and extensively than covalently bound acetylaminofluorene. In human cells, for example, about 50% of the dimers were excised from DNA in 1 hr while only 25-50% of the chemically induced lesions were excised from DNA after 48 hr. Surprisingly mouse cells, which remove few dimers, were about as competent as control human fibroblasts at removing acetylaminofluorene lesions; however, xeroderma pigmentosum cells (group D) removed fewer N-acetoxy-2-acetylaminofluorene-induced lesions than control human cells. Our data raise the possibility of separate repair processes for these two types of lesions and suggest that their expression may be under similar genetic control in human cells.
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PMID:Differences in removal of acetylaminofluorene and pyrimidine dimers from the DNA of cultured mammalian cells. 26 96

Osmotic disruption of confluent cultured human fibroblasts that have been irradiated or exposed to chemical carcinogens allows the specific measurement of repair DNA synthesis using dTTP as a precursor. Fibroblasts similarly prepared from various xeroderma pigmentosum cell lines show the deficiencies of UV-induced DNA synthesis predicted from in vivo studies, while giving normal responses to methyl methanesulfonate. A pyrimidine-dimer-specific enzyme, T4 endonuclease V, stimulated the rate of UV-induced repair synthesis with normal and xeroderma pigmentosum cell lines. This system should prove useful for identifying agents that induce DNA repair, and cells that respond abnormally to such induction. It should also be applicable to an in vitro complementation assay with repair-defective cells and proteins obtained from repair-proficient cells. Finally, by using actively growing fibroblasts and thymidine in the system, DNA replication can be measured and studied in vitro.
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PMID:A cell-free assay measuring repair DNA synthesis in human fibroblasts. 27 17

Xeroderma pigmentosum is an autosomal recessive disease in which DNA repair processes are defective. All xeroderma pigmentosum patients develop premature aging of sun-exposed skin, and some develop neurological abnormalities due to premature death of nerve cells. Sensitivity to ultraviolet radiation of 24 xeroderma pigmentosum fibroblast strains was studied in vitro by measuring each strain's ability to divide and form colonies after irradiation. The most sensitive strains were derived from patients who had an early onset of neurological abnormalities; less sensitive strains were from patients with a later onset; and the most resistant strains were from patients without neurological abnormalities. The UV sensitivities of strains from each member of a sibling pair with xeroderma pigmentosum were identical, indicating that UV sensitivity of xeroderma pigmentosum strains is determined by the patient's inherited DNA repair defect. The results suggest that effective DNA repair is required to maintain the functional integrity of the human nervous system by preventing premature death of neurons.
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PMID:Xeroderma pigmentosum neurological abnormalities correlate with colony-forming ability after ultraviolet radiation. 27 25

The repair mode of DNA replication has been demonstrated in isolated nuclei from UV-irradiated human cells. Nuclei are incubated in a mixture containing [(3)H]thymidine triphosphate and bromodeoxyuridine triphosphate in a 1:5 ratio. The (3)H at the density of parental DNA in alkaline CsCl density gradients is then a measure of repair. In nuclei prepared from WI38 cells 30 min after irradiation, repair replication is UV dependent and proceeds at approximately the in vivo rate for 5 min. Repair replication is reduced in irradiated nuclei or in nuclei prepared immediately after irradiation. It is Mg(2+)-dependent and stimulated by added ATP and deoxyribonucleoside triphosphates. No repair replication is observed in nuclei from xeroderma pigmentosum (complementation group A) cells. However, upon addition of coliphage T4 endonuclease V, which specifically nicks DNA containing pyrimidine dimers, repair replication is observed in nuclei from irradiated xeroderma pigmentosum cells and is stimulated in WI38 nuclei. The reaction then persists for an hour and is dependent upon added ATP and deoxyribonucleoside triphosphates. The repair label is in stretches of roughly 35 nucleotides, as it is in intact cells. Added pancreatic DNase does not promote UV-dependent repair synthesis. Our results support the view that xeroderma pigmentosum (group A) cells are defective in the incision step of the DNA excision repair pathway, and demonstrate the utility of this system for probing DNA repair mechanisms.
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PMID:Phage T4 endonuclease V stimulates DNA repair replication in isolated nuclei from ultraviolet-irradiated human cells, including xeroderma pigmentosum fibroblasts. 27 29

In 31 families of xeroderma pigmentosum (XP) patients, significantly more blood relatives than spouse controls had had nonmelanoma skin cancer. These family data support the hypothesis that heterozygosity for XP genes may predispose persons to skin cancer, particularly in association with substantial exposure to sunlight.
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PMID:Cancer in families with xeroderma pigmentosum. 28 13

DNA synthesis in normal cells and in excision-defective and variant xeroderma pigmentosum cells was investigated after irradiation with ultraviolet light. The sizes of DNA synthesized during brief pulses of [3H]thymidine 1-2 hr after irradiation were decreased, the xeroderma pigmentosum variant showing the smallest molecular weight. Once synthesized, however, labeled DNA increased in size at the same rat as control in all cell strains, and the rate was relatively insensitive to caffeine. After 2-3 hr, labeled DNA in each cell type reached a maximum size that was less than that in control cells, indicating the presence of long-lived blocks to DNA chain growth. This kind of experiment (pulse-chase) has in the past been used to investigate a repair process believed to be associated with the bypass of damaged sites in parental DNA: postreplication repair. We present an alternative model that does not involve a specific postreplication repair mechanism, but involve a specific postreplication repair mechanism, but involves normal chain elongation and termination mechanisms in which we conceive that dimers and other damaged sites act as well-or-nothing blocks to the progress of replication forks. No evidence could be found for any inducible process that enhanced the bypass of damaged sites.
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PMID:Postreplication repair: questions of its definition and possible alteration in xeroderma pigmentosum cell strains. 29 Oct 51


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