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)

Xeroderma pigmentosum (XP), a genetically heterogeneous human disease, results from a defect in nucleotide excision repair of ultraviolet-damaged DNA. XP patients are extremely sensitive to sunlight and suffer from a high incidence of skin cancers. Cell fusion studies have identified seven XP complementation groups, A-G. Group D is of particular interest as mutations in this gene can also cause Cockayne's syndrome and trichothiodystrophy. The XPD gene was initially named ERCC2 (excision repair cross complementing) as it was cloned using human DNA to complement the ultraviolet sensitivity of a rodent cell line. We have purified the XPD protein to near homogeneity and show that it possesses single-stranded DNA-dependent ATPase and DNA helicase activities. We tested whether XPD can substitute for its yeast counterpart RAD3, which is essential for excision repair and for cell viability. Expression of the XPD gene in Saccharomyces cerevisiae can complement the lethality defect of a mutation in the RAD3 gene, suggesting that XPD is an essential gene in humans.
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PMID:Human xeroderma pigmentosum group D gene encodes a DNA helicase. 841 72

The human BTF2 basic transcription factor (also called TFIIH), which is similar to the delta factor in rat and factor b in yeast, is required for class II gene transcription. A strand displacement assay was used to show that highly purified preparation of BTF2 had an adenosine triphosphate-dependent DNA helicase activity, in addition to the previously characterized carboxyl-terminal domain kinase activity. Amino acid sequence analysis of the tryptic digest generated from the 89-kilodalton subunit of BTF2 indicated that this polypeptide corresponded to the ERCC-3 gene product, a presumed helicase implicated in the human DNA excision repair disorders xeroderma pigmentosum and Cockayne's syndrome. These findings suggest that transcription and nucleotide excision repair may share common factors and hence may be considered to be functionally related.
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PMID:DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. 846 98

The molecular pathway of p53-dependent apoptosis (programmed cell death) is poorly understood. Because p53 binds to the basal transcription-repair complex TFIIH and modulates its DNA helicase activities, we hypothesized that TFIIH DNA helicases XPB and XPD are members of the p53-mediated apoptotic pathway. Whereas transfer of a wild-type p53 expression vector by microinjection or retroviral infection into primary normal human fibroblasts resulted in apoptosis, primary fibroblasts from individuals with xeroderma pigmentosum (XP), who are deficient in DNA repair and have germ-line mutations in the XPB or XPD gene, but not in the XPA or XPC gene, have a deficiency in the apoptotic response. This deficiency can be rescued by transferring the wild-type XPB or XPD gene into the corresponding mutant cells. XP-D lymphocytes also have a decreased apoptotic response to DNA damage by adriamycin, indicating a physiologically relevant deficiency. The XP-B or XP-D mutant cells undergo a normal apoptotic response when microinjected with the Ich-L, and ICE genes. Analyses of p53 mutants and the effects of microinjected anti-p53 antibody, Pab421, indicate that the carboxyl terminus of p53 may be required for apoptosis. Direct microinjection of the p53 carboxy-terminal-derived peptide (amino acid residues 319-393) resulted in apoptosis of primary normal human fibroblasts. These results disclose a novel pathway of p53-induced apoptosis.
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PMID:The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. 867 9

A search of the Human Genome Sciences database of expressed sequence-tagged DNA fragments, for sequences containing homology to known yeast DNA recombination and repair genes, yielded a cDNA fragment with high homology to RAD54. Here we describe the complete cDNA sequence and the characterization of the genomic locus coding for the human homologue of the yeast RAD54 gene (hRAD54). The yeast RAD54 belongs to the RAD52 epistasis group and appears to be involved in both DNA recombination and repair. The hRAD54 gene maps to chromosome 1p32 in a region of frequent loss of heterozygosity in breast tumors and encodes a protein of M(r) 93,000 that displays 52% identity to the yeast RAD54 protein. The hRAD54 protein sequence additionally contains all seven of the consensus segments of a superfamily of proteins with presumed or proven DNA helicase activity. Mutations in genes with consensus helicase homology have been found in cancer-prone syndromes such as xeroderma pigmentosum and Bloom syndrome as well as Werner's syndrome, in which patients age prematurely, and the X-linked mental retardation with alpha-thalassemia syndrome, ATR-X. We have examined the hRAD54 gene in several breast tumors and breast tumor cell lines and, although the gene region appears to be deleted in several tumors, at present we have found no coding sequence mutations.
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PMID:Characterization of the human homologue of RAD54: a gene located on chromosome 1p32 at a region of high loss of heterozygosity in breast tumors. 919 13

During nucleotide excision repair in human cells, a damaged DNA strand is cleaved by two endonucleases, XPG on the 3' side of the lesion and ERCC1-XPF on the 5' side. These structure-specific enzymes act at junctions between duplex and single-stranded DNA. ATP-dependent formation of an open DNA structure of approximately 25 nt around the adduct precedes this dual incision. We investigated the mechanism of open complex formation and find that mutations in XPB or XPD, the DNA helicase subunits of the transcription and repair factor TFIIH, can completely prevent opening and dual incision in cell-free extracts. A deficiency in XPC protein also prevents opening. The absence of RPA, XPA or XPG activities leads to an intermediate level of strand separation. In contrast, XPF or ERCC1-defective extracts open normally and generate a 3' incision, but fail to form the 5' incision. This same repair defect was observed in extracts from human xeroderma pigmentosum cells with an alteration in the C-terminal domain of XPB, suggesting that XPB has an additional role in facilitating 5' incision by ERCC1-XPF nuclease. These data support a mechanism in which TFIIH-associated helicase activity and XPC protein catalyze initial formation of the key open intermediate, with full extension to the cleavage sites promoted by the other core nucleotide excision repair factors. Opening is followed by dual incision, with the 3' cleavage made first.
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PMID:Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. 935 36

The xeroderma pigmentosum (XP) group D (XPD) gene encodes a DNA helicase that is a subunit of the transcription factor IIH complex, involved both in nucleotide excision repair of UV-induced DNA damage and in basal transcription initiation. Point mutations in the XPD gene lead either to the cancer-prone repair syndrome XP, sometimes in combination with a second repair condition; Cockayne syndrome; or the non-cancer-prone brittle-hair disorder trichothiodystrophy. To study the role of XPD in nucleotide excision repair and transcription and its implication in human disorders, we isolated the mouse XPD gene and generated a null allele via homologous recombination in embryonic stem cells by deleting XPD helicase domains IV-VI. Heterozygous cells and mice are normal without any obvious defect. However, when intercrossing heterozygotes, homozygous XPD mutant mice were selectively absent from the offspring. Furthermore, we could not detect XPD-/- embryos at day 7.5 of development. In vitro growth experiments with preimplantation-stage embryos obtained from heterozygous intercrosses showed a significantly higher fraction of embryos that died at the two-cell stage, compared to wild-type embryos. These results establish the essential function of the XPD protein in mammals and in cellular viability and are consistent with the notion that only subtle XPD mutations are found in XP, XP/Cockayne syndrome, and trichothiodystrophy patients.
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PMID:Disruption of the mouse xeroderma pigmentosum group D DNA repair/basal transcription gene results in preimplantation lethality. 942 63

The human gene XPB, defective in xeroderma pigmentosum patients complementation group B, encodes a DNA helicase involved in several DNA metabolic pathways, including DNA repair and transcription. The high conservation of this gene has allowed the cloning of homologs in various species, such as mouse, yeast and Drosophila. Not much information on the molecular basis of nucleotide excision repair in plants is available, but these organisms may have similar mechanisms to other eukaryotes. A homolog of XPB was isolated in Arabidopsis thaliana by using polymerase chain reaction (PCR) with degenerate oligonucleotides based on protein domains which are conserved among several species. Screening of an Arabidopsis cDNA library led to the identification and isolation of a cDNA clone with 2670 bp encoding a predicted protein of 767 amino acids, denoted araXPB. Genomic analysis indicated that this is a nuclear single copy gene in plant cells. Northern blot with the cDNA probe revealed a major transcript which migrated at approx. 2,800 b, in agreement with the size of the cDNA isolated. The araXPB protein shares approximately 50% identical and 70% conserved amino acids with the yeast and human homologs. The plant protein maintains all the functional domains found in the other proteins, including nuclear localization signal, DNA-binding domain and helicase motifs, suggesting that it might also act as part of the RNA transcription apparatus, as well as nucleotide excision repair in plant cells.
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PMID:Cloning of a cDNA from Arabidopsis thaliana homologous to the human XPB gene. 952 67

Organisms use different mechanisms to detect and repair different types of DNA damage, and different species vary in their sensitivity to DNA damaging agents. The cellular slime mold Dictyostelium discoideum has long been recognized for its unusual resistance to UV and ionizing radiation. We have recently cloned three nucleotide excision repair (NER) genes from Dictyostelium , the rep B, D and E genes (the homologs of the human xeroderma pigmentosum group B, D and E genes, respectively). Each of these genes has a unique pattern of expression during the multicellular development of this organism. We have now examined the response of these genes to DNA damage. The rep B and D DNA helicase genes are rapidly and transiently induced in a dose dependent manner following exposure to both UV-light and the widely used chemotherapeutic agent cisplatin. Interestingly, the rep E mRNA level is repressed by UV but not by cisplatin, implying unique signal transduction pathways for recognizing and repairing different types of damage. Cells from all stages of growth and development display the same pattern of NER gene expression following exposure to UV-light. These results suggest that the response to UV is independent of DNA replication, and that all the factors necessary for rapid transcription of these NER genes are either stable throughout development, or are continuously synthesized. It is significant that the up-regulation of the rep B and D genes in response to UV and chemical damage has not been observed to occur in cells from other species. We suggest that this rapid expression of NER genes is at least in part responsible for the unusual resistance of Dictyostelium to DNA damage.
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PMID:Rapid changes of nucleotide excision repair gene expression following UV-irradiation and cisplatin treatment of Dictyostelium discoideum. 964 25

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.
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PMID:The evolution of aging: a new approach to an old problem of biology. 979 99

The human XPB DNA helicase is a subunit of the DNA repair/basal transcription factor TFIIH, involved in early steps of the nucleotide excision repair pathway. Two distinct clinical phenotypes, xeroderma pigmentosum associated with Cockayne's syndrome (XP/CS) and trichothiodystrophy (TTD), can be due to mutations in the XPB gene. In the present work, we studied cellular DNA repair properties of skin fibro-blasts from two patients mutated in the XPB gene: an XP/CS patient cell (XPCS2BA) with a T296C (F99S) transition and a TTD patient cell (TTD6VI) exhibiting an A355C (T119P) transversion. Both cells are clearly associated with different levels of alterations in their response to UV light. To establish the relationship between the relative expression level of these two alleles and DNA repair properties, we transfected SV40-transformed XPCS2BA (XPCS2BASV) cells with a plasmid (pTTD6VI) carrying the XPB-A355C cDNA and examined DNA repair properties after UV irradiation (cell survival, unscheduled DNA synthesis and kinetics of photoproduct removal) in stable transfectants. We isolated three clones, which express the XPB-A355C gene (Cl-5) or the XPB-T296C gene (Cl-14) or both genes (Cl-19). This con-stitutes a model system allowing us to correlate the relative expression levels of the XPB-A355C (TTD) and XPB-T296C (XP/CS) genes with various DNA repair properties. Overexpression of the XPB-A355C (TTD) gene in an XP/CS cell gives rise to a cellular phenotype of increased repair similar to that of TTD6VI cells, while equal expression of the two mutated genes leads to an intermediate cellular phenotype between XP/CS and TTD.
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PMID:The relative expression of mutated XPB genes results in xeroderma pigmentosum/Cockayne's syndrome or trichothiodystrophy cellular phenotypes. 1033 46

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