UMLS:C0043346 - FACTA Search

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Query: UMLS:C0043346 (xeroderma pigmentosum)
2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clonogenic survival response to 254-nm ultraviolet light was measured in 2 strains of repair-proficient normal human fibroblasts and 4 strains of xeroderma pigmentosum (XP) fibroblasts belonging to complementation groups A, C, D and variant. In all strains except XPA, cells irradiated in plateau phase and subcultured immediately were much more resistant to the lethal effect of UV than cells irradiated in the exponential phase of growth. Typically, 10-20% of plateau-phase cells were extremely resistant. When the cultures were held in plateau phase for 24 h after irradiation and before subculture, there was a further enhance of survival. By use of a UV-specific endonuclease assay, no difference was found in the number of DNA lesions induced in exponentially growing and plateau cultures by the same dose of UV light. Thus plateau-phase cells appear to be more efficient in their DNA-repair capability than cells in exponential growth. XP group A cells were uniquely found to be deficient in the processes which lead to plateau-phase resistance. Since plateau-phase repair was not lacking in XP groups C, D and variant, it may be related to a DNA-repair process different from that which is responsible for the overall UV sensitivity of these cells.
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PMID:Resistance of plateau-phase human normal and xeroderma pigmentosum fibroblasts to the cytotoxic effect of ultraviolet light. 52 80

A genetic linkage map of human chromosome 9q, spanning a sex-equal distance of 125 cM, has been developed by genotyping 26 loci in the Venezuelan Reference Pedigree. The loci include 12 anonymous microsatellite markers reported by Kwiatkowski et al. (1992), several classical systems previously assigned to chromosome 9q, and polymorphisms for the genes tenacin (HXB), gelsolin (GSN), adenylate kinase 1 (AK1), arginosuccinate synthetase (ASS), ABL oncogene (ABL1), ABO blood group (ABO), and dopamine beta-hydroxylase (DBH). Only a marginally significant sex difference is found along the entire length of the map and results from one interval, between D9S58 and D9S59, that displays an excess of female recombination. A comparison of the genetic map to the existing physical data suggests that there is increased recombination in the 9q34 region with a recombination event occurring every 125-400 kb. This map should be useful in further characterizing the relationship between physical distance and genetic distance, as well as for genetic linkage studies of diseases that map to chromosome 9q, including multiple self-healing squamous epithelioma (MSSE), Gorlin syndrome (NBCCS), xeroderma pigmentosum (XPA), nail-patella syndrome (NPS1), torsion dystonia (DYT1), and tuberous sclerosis (TSC1).
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PMID:A genetic linkage map of human chromosome 9q. 142 99

Sib patients with xeroderma pigmentosum (XP), XP90TO (42 years old, male) and XP92TO (40 years old, female, were assigned to group F by the complementation analysis in hybridized heterodikaryons. The XP90TO and XP92TO fibroblasts exhibited the typical XPF characteristics of a threefold higher sensitivity to the lethal effect of 254 nm UV and a reduced level of 12% unscheduled DNA synthesis (UDS) compared with normal cells. Clinically, both patients manifested moderate to severe acute sun sensitivity by age 8, pigmented freckles by age 10 and skin malignancies at higher ages (6 basaliomas at 42 years in XP90TO; 1 basalioma at 41 years in XP92TO). Despite the still currently sun-sensitive state, the patients showed normal minimal erythema dose (MED) at monochromatic wavelengths of 290, 300 and 305 nm but abnormally delayed peaking of erythema reaction at 48 h after exposure. After irradiation with more than 3 MED, XP92TO showed a long persistence of induced erythema for at least 7 days. A review of the 16 reported XPF patients indicated mild skin manifestations, no neurological abnormalities, and more delayed skin carcinogenesis at a lower frequency than that in XPA patients. In addition, we have collected clinical information from Japanese XP patients in rare complementation groups D and E and reviewed their clinical and photobiological characteristics.
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PMID:Late onset of skin cancers in 2 xeroderma pigmentosum group F siblings and a review of 30 Japanese xeroderma pigmentosum patients in groups D, E and F. 266 29

Following transfection of genomic mouse DNA into an SV40 transformed fibroblast cell line from a patient with Xeroderma pigmentosum (complementation group A, XPA), a single UV resistant cell clone was isolated out of a total of 10(4) independent transfectants. The recipient XPA cell line has as yet not produced spontaneous revertants among 2.2 x 10(8) cells. The isolated cell clone contains 50-70 kb of mouse sequences which are heavily amplified (500-fold), and has acquired both intermediate resistance to UV killing and intermediate unscheduled DNA synthesis (UDS) capacity. By continued passage without selective pressure, cells were generated, which had lost both the dominant marker gene and repetitive mouse sequences. Single colonies of these cells were still intermediately resistant to UV suggesting that either undetected unique mouse DNA had segregated from the bulk of repetitive DNA, or, more likely, that the initially isolated transfectant was a spontaneous revertant. This documents that a persuasive clone isolated can still be a false positive (spontaneous revertant) and that an extremely laborious approach may lead into a dead end.
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PMID:A promising genomic transfectant into Xeroderma pigmentosum group A with highly amplified mouse DNA and intermediate UV resistance turns revertant. 271 87

Repair-proficient human cells can be sensitized to exposure to UV radiation at 254 nm by postirradiation incubation in the presence of the eukaryotic alpha polymerase inhibitor, aphidicolin. The degree of sensitization has been examined in cells cultured from humans suffering from various types of sun-sensitive syndromes. Xeroderma pigmentosum (XP) variant and Bloom's cell lines (both excision proficient) were strongly sensitized by aphidicolin. An excision repair proficient Cockayne's cell line and a deficient XPD line were both sensitized to a level similar to the sensitivity of excision deficient XPA cells. In contrast, three XPC cell lines which show intermediate UV-induced repair replication and UV sensitivity were sensitized little (in one case) or not at all (in two cases) to UV by postirradiation inhibition of the alpha polymerase. These results lead us to conclude that there are two independent pathways of biologically effective excision repair, the major one of which involves the alpha polymerase and a second, less efficient and slower pathway which is independent of the alpha polymerase and which is the only pathway operating in two of the three XPC strains tested. The rates of biologically effective excision repair were similar in normal, XP variant, and Cockayne's cell lines, but these rates were considerably higher than published rates of dimer excision measured under similar conditions.
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PMID:Evidence for two independent pathways of biologically effective excision repair from its rate and extent in cells cultured from sun-sensitive humans. 310 32

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

The formation of DNA strand breaks was characterized in human fibroblasts prepared by several methods. In quiescent monolayer cultures of normal human fibroblasts (NHF), exposure to 254 nm radiation (UV) caused the rapid appearance of DNA strand breaks as monitored by alkaline elution analysis. Maximal levels of DNA breaks were seen 30 min after 10 J/m2; thereafter, strand breaks disappeared. Breakage soon after irradiation appeared to saturate at fluences above 10 J/m2. Xeroderma pigmentosum fibroblasts belonging to complementation group A (XPA) did not display this response which reflects operations of the nucleotidyl DNA excision repair pathway. When fibroblast strains were released from culture dishes by enzymatic digestion with trypsin or by scraping with a rubber policeman, UV-dependent DNA breakage displayed altered dose and time responses. Few breaks were detected in detached preparations of NHF after 10 J/m2 indicating inactivation of nucleotidyl DNA excision repair. The fluence response in detached fibroblasts was linear up to an incident fluence of 100 J/m2. Moreover, after 25 or 50 J/m2, strand breaks accumulated as a linear function of time for up to 2 h after irradiation. This UV-dependent and time-dependent incision activity was also observed in XPA monolayers and released-cell preparations. In permeable fibroblast preparations, DNA breaks accumulated in unirradiated cells that had been released with trypsin or by scraping. Permeabilization in situ saponin to open the plasma membrane produced a cell preparation that accumulated fewer UV-independent breaks. In saponin-permeabilized NHF that were irradiated with 10 J/m2, UV-dependent strand incision activity occurred at about 30% of the rate of incision seen in intact monolayer NHF. These results reveal at least 3 DNA strand incision activities in human fibroblast preparations of which only one reflects operation of the nucleotidyl DNA excision repair pathway.
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PMID:Formation of DNA strand breaks in UV-irradiated human fibroblast preparations. 360 Jun 82

DNA double-strand breaks (DSBs) are formed in normal human IMR-90 cells during repair incubation after 100 and 300 J.m-2 of ultraviolet light. By contrast, no DSBs are formed after exposure to ultraviolet light in human XPA cells (from a patient with xeroderma pigmentosum complementation group A), which are unable to excise pyrimidine dimers. The DSBs are not due to immediate cell death, because all the cells excluded trypan blue at the time of assay and because XPA cells, which are much more sensitive to ultraviolet light than are IMR-90 cells, did not form DSBs after exposure to ultraviolet light. The DSBs do not appear to be due to either DNA synthesis or cellular single-strand endonucleases. We suggest that repair-induced DSBs would be potent lesions that might lead to cytotoxicity, chromosome aberrations, deletion mutations, and perhaps cellular transformation.
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PMID:DNA double-strand breaks induced in normal human cells during the repair of ultraviolet light damage. 626 1

Analysis of the distribution of cells through the phases of the cell cycle by DNA flow cytofluorimetry has been utilized to investigate the effects of ultraviolet (UV) irradiation on cell-cycle progression in normal and UV-sensitive lymphoblastoid cell lines. In time-course studies only slight perturbation of DNA distribution was seen in normal cells, or UV-sensitive familial melanoma (FM) lines in the 48 h following irradiation. Xeroderma pigmentosum (XPA) excision-deficient cells showed a large increase in the proportion of cells in S phase 16-40 h post-irradiation. XP variant (XPV) cells were blocked in G1 and S phases with the complete absence of cells with G2 DNA content 16-28 h after irradiation. By 48 h post-irradiation the DNA distribution of XPA and XPV cells had returned to that of an unirradiated control. When colcemid was added to the cultures immediately after irradiation to prevent mitotic cells dividing and re-entering the cell cycle, progression through the first cycle after irradiation was followed. UV irradiation did not affect the rate of movement of cells out of G1 into S phase in normal, FM or XPA cells. The proportion of cells in S phase was increased in UV-irradiated cultures in these cell types and the number of cells entering the G2 + M compartment was reduced. In UV-irradiated cultures of XPV cells a large proportion of cells was blocked in G1. The rate of accumulation of cells with G2 DNA content was equal to that of the control until 4 h post-irradiation, thereafter falling below the control. Thus XPV cells in S phase at the time of irradiation complete DNA synthesis to reach G2 DNA content. However, cells irradiated in G1 are blocked from entry into S. These results suggest that there is a defect in XPV cells that affects a step prior to the onset of DNA replication.
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PMID:Effects of ultraviolet irradiation on the cell cycle in normal and UV-sensitive cell lines with reference to the nature of the defect in xeroderma pigmentosum variant. 663 57

The processing of covalent aflatoxin B1 (AFB1)-DNA adducts was investigated in confluent normal fibroblasts (NF) and xeroderma pigmentosum skin fibroblasts of Complementation Group A (XPA) following treatment with rat liver microsome-activated AFB1 for 30 min. Following rapid DNA isolation at slightly acidic pH by a new filter technique, more than 90% of the adducts corresponded to 2,3-dihydro-2-(N7-guanyl)-3-hydroxy-AFB1 (AFB1-N7-Gua) according to the analysis of acid hydrolysates by high-pressure liquid chromatography. The changes in adduct concentration and composition were compared between DNA isolated immediately following AFB1 treatment and incubated at neutrality in vitro and DNA in situ in the cell isolated after different lengths of incubation. The following conclusions were reached from the observed differences in the kinetics of adduct removal from free DNA and DNA in situ in NF and XPA: (a) AFB1-N7-Gua is removed spontaneously and enzymatically in NF but probably only spontaneously in XPA. This result suggests that these lesions are removed via nucleotide excision repair in NF; (b) the putative 2,3-dihydro-2(N5-formyl-2',5',6'-triamino-4'-oxo-N5-pyrimidyl)-3-hydroxyaflatoxin B1 is formed in a secondary reaction from AFB1-N7-Gua in vitro and in situ in the cell. It accumulates more rapidly and to a greater extent in XPA than in NF and persists in both cells types over prolonged periods. The reaction of AFB1-N7-Gua to 2,3-dihydro-2-(N5-formyl-2',5'6'-triamino-4'-oxo-N5-pyrimidyl)-3-hydroxyaflatox in B1 represents the transformation of a repairable lesion to a nonrepairable, persistent lesion.
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PMID:Excision repair of aflatoxin B1-DNA adducts in human fibroblasts. 679 65

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