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)

TFIIH is a multiprotein factor involved in transcription and DNA repair and is implicated in DNA repair/transcription deficiency disorders such as xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Eight out of the nine genes encoding the subunits forming TFIIH have already been cloned. We report here the identification, cDNA cloning and gene structure of the 52 kDa polypeptide and its homology with the yeast counterpart TFB2. This protein, along with p89/XPB, p62, p44 and p34, forms the core of TFIIH. Moreover, using in vitro reconstituted transcription and nucleotide excision repair (NER) assays and microinjection experiments, we demonstrate that p52 is directly involved in both transcription and DNA repair mechanisms in vitro and in vivo.
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PMID:Cloning and characterization of p52, the fifth subunit of the core of the transcription/DNA repair factor TFIIH. 911 47

An auxiliary protein of DNA polymerases delta and epsilon, the proliferating cell nuclear antigen (PCNA), is necessary for efficient DNA replication in vivo and in vitro, and also for the repair synthesis in vitro, but its role in the excision repair of genome in vivo is not exactly established. In S-phase of unirradiated cells, PCNA is tightly bound to focal centers of DNA replication and is not removed by treatment with detergent Triton X-100, but is completely extracted from non-S-phase cells by the indicated detergent. It was shown earlier that after UV-irradiation PCNA could not be removed by the detergent even from non-S-phase cells. It was interpreted as the evidence of PCNA integration into the repair complex and of the participation of this protein in repair synthesis in vivo. In the present work the data were obtained indicating that the role of PCNA in cell response to UV-damage was not confined only to its possible involvement in repair synthesis. With the help of confocal microscopy it was established that in Triton X-100-extracted normal cells PCNA did not colocalize with the well known excision repair protein XPB/ERCC3, defective in cells from Xeroderma pigmentosum (complementation group B) patients. XPB-protein is induced by UV-irradiation in normal cells, and this induction is not observed in repair deficient cells. However, in such cells UV-light induces a detergent-resistant form of PCNA, and this form is obviously not connected with repair. It cannot be excluded that a rapid PCNA immobilization immediately after UV-irradiation of cells is needed for the facilitation of photochemical damage bypass during the subsequent replication of genome.
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PMID:[The dual function of the proliferating cell nuclear antigen (PCNA) in the response of human cells to UV damages]. 916 4

DNA helicases are essential to many cellular processes including recombination, replication and transcription, and some helicases function in multiple processes. The helicases encoded by the Xeroderma pigmentosum (XP) B and D genes function in both nucleotide excision repair and transcription initiation. Mutations that affect the repair function of these proteins result in XP while mutations affecting transcription result in neurological and developmental abnormalities, although the underlying molecular and cellular basis for these phenotypes is not well understood. To better understand the developmental roles of these genes, we have now identified and characterized the rep B and rep D genes from the cellular slime mold Dictyostelium discoideum . Both genes encode DNA helicases of the SF2 superfamily of helicases. The rep D gene contains no introns and the rep B gene contains only one intron, which makes their genomic structures dramatically different from the corresponding genes in mammals and fish. However the predicted Dictyostelium proteins share high homology with the human XPB and XPD proteins. The single copy of the rep B and D genes map to chromosomes 3 and 1, respectively. The expression of rep B and D (and the previously isolated rep E) genes during multicellular development was examined, and it was determined that each rep gene has a unique pattern of expression, consistent with the idea that they have specific roles in development. The pattern and extent of expression of these genes was not affected by the growth history of the cells, implying that the expression of these genes is tightly regulated by the developmental program. The expression of the rep genes is a very early step in development and may well represent a key event in the initiation of development in this organism.
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PMID:Differential developmental expression of the rep B and rep D xeroderma pigmentosum related DNA helicase genes from Dictyostelium discoideum. 917 Oct 87

Mutations in the basal transcription initiation/DNA repair factor TFIIH are responsible for three human disorders: xeroderma pigmentosum (XP), cockayne syndrome (CS) and trichothiodystrophy (TTD). The non-repair features of CS and TTD are thought to be due to a partial inactivation of the transcription function of the complex. To search for proteins whose interaction with TFIIH subunits is disturbed by mutations in patients we used the yeast two-hybrid system and report the isolation of a novel XPB interacting protein, SUG1. The interaction was validated in vivo and in vitro in the following manner. (i) SUG1 interacts with XPB but not with the other core TFIIH subunits in the two-hybrid assay. (ii) Physical interaction is observed in a baculovirus co-expression system. (iii) In fibroblasts under non-overexpression conditions a portion of SUG1 is bound to the TFIIH holocomplex as deduced from co-purification, immunopurification and nickel-chelate affinity chromatography using functional tagged TFIIH. Furthermore, overexpression of SUG1 in normal fibroblasts induced arrest of transcription and a chromatin collapse in vivo. Interestingly, the interaction was diminished with a mutant form of XPB, thus providing a potential link with the clinical features of XP-B patients. Since SUG1 is an integral component of the 26S proteasome and may be part of the mediator, our findings disclose a SUG1-dependent link between TFIIH and the cellular machinery involved in protein modelling/degradation.
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PMID:The XPB subunit of repair/transcription factor TFIIH directly interacts with SUG1, a subunit of the 26S proteasome and putative transcription factor. 917 76

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) cells have specific DNA repair defects. We had previously analyzed repair rates of cyclobutane pyrimidine dimers at nucleotide resolution along the human JUN gene in normal fibroblasts and found very efficient repair of sequences near the transcription initiation site but slow repair along the promoter. To investigate sequence-specific repair rate patterns in XP and CS cells, we conducted a similar analysis in XPA, XPB, XPC, XPD, and CSB fibroblasts. XPA cells were almost completely repair-deficient at all sequences analyzed. XPC cells repaired only the transcribed DNA strand beginning at position -20 relative to the transcription start site. Both XBP and XPD cells were deficient in repair of nontranscribed DNA and also very inefficiently repaired the transcribed strand including sequences near the transcription start site. CSB cells exhibited rapid repair near the transcription initiation site but were deficient in repair of sequences encountered by RNA polymerase during elongation (beginning at position +20). Since transcription of the JUN gene was UV-induced in all fibroblast strains, including CSB, the defective repair of the transcribed strand in CSB cannot be explained by a lack of transcription; rather, it appears to be a true DNA repair defect.
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PMID:Sequence-specific and domain-specific DNA repair in xeroderma pigmentosum and Cockayne syndrome cells. 925 97

The hereditary disease Cockayne syndrome (CS) is a complex clinical syndrome characterized by arrested post-natal growth as well as neurological and other defects. The CSA and CSB genes are implicated in this disease. The clinical features of CS can also accompany the excision repair-defective hereditary disorder xeroderma pigmentosum (XP) from genetic complementation groups B, D or G. The XPB and XPD proteins are subunits of RNA polymerase II (RNAP II) transcription factor IIH (TFIIH). We show here that extracts of CS-A and CS-B cells, as well as those from XP-B/CS cells, support reduced levels of RNAP II transcription in vitro and that this feature is dependent on the state or quality of the template.
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PMID:Reduced RNA polymerase II transcription in extracts of cockayne syndrome and xeroderma pigmentosum/Cockayne syndrome cells. 927 84

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

With the aim to devise a long-term gene therapy protocol for skin cancers in individuals affected by the inherited autosomal recessive xeroderma pigmentosum we transferred the human DNA repair XPA, XPB/ERCC3 and XPC cDNAs, by using the recombinant retroviral vector LXSN, into primary and immortalized fibroblasts obtained from two XP-A, one XP-B (associated with Cockayne's syndrome) and two XP-C patients. After transduction, the complete correction of DNA repair deficiency and functional expression of the transgenes were monitored by UV survival, unscheduled DNA synthesis and recovery of RNA synthesis, and Western blots. The results show that the recombinant retroviruses are highly efficient vectors to transfer and stably express the human DNA repair genes in XP cells and correct the defect of DNA repair of group A, B and C. With our previous results with XPD/ERCC2, the present work extends further promising issues for the gene therapy strategy for most patients suffering from this cancer-prone syndrome.
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PMID:Retrovirus-mediated gene transfer corrects DNA repair defect of xeroderma pigmentosum cells of complementation groups A, B and C. 941 14

TFIIH is a high molecular weight complex with a remarkable dual function in nucleotide excision repair and initiation of RNA polymerase II transcription. Mutations in the largest subunits, the XPB and XPD helicases, are associated with three inherited disorders: xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy. To facilitate the purification and biochemical characterization of this intricate complex, we generated a cell line stably expressing tagged XPB, allowing the immunopurification of the XPB protein and associated factors. Addition of two tags, a N-terminal hexameric histidine stretch and a C-terminal hemagglutinin epitope, to this highly conserved protein did not interfere with its functioning in repair and transcription. The hemagglutinin epitope allowed efficient TFIIH immunopurification to homogeneity from a fractionated whole cell extract in essentially one step. We conclude that the predominant active form of TFIIH is composed of nine subunits and that there is one molecule of XPB per TFIIH complex. The affinity-purified complex exhibits all expected TFIIH activities: DNA-dependent ATPase, helicase, C-terminal domain kinase, and participation in in vitro and in vivo nucleotide excision repair and in vitro transcription. The affinity purification procedure described here is fast and simple, does not require extensive chromatographic procedures, and yields highly purified, active TFIIH.
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PMID:Affinity purification of human DNA repair/transcription factor TFIIH using epitope-tagged xeroderma pigmentosum B protein. 942 74

Most of the genes involved in the pathogenesis of the DNA replication and repair syndromes have now been cloned, and our understanding of the basis for the pleiotropic phenotype associated with many of these syndromes has rapidly and dramatically expanded. The elucidation of the specific interactions between proteins that comprise the transcription factor complex TFIIH raises the possibility that nucleotide excision repair, RNA polymerase II transcription, and cell cycle control are connected. Defects in the XPB, XPD, and XPG genes can result in three different syndromes, xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy, depending on the specific mutation involved. The recent cloning of the genes involved in Bloom syndrome (BLM) and Werner syndrome (WRN) show that both are DNA and RNA helicases with homology to each other and to other DExH box helicases, yet the mechanism by which defects in these genes cause such different phenotypes is not yet understood. The ataxia-telangiectasia gene (ATM) is involved in a variety of signal transduction pathways that regulate the cellular response to normal proliferative stimuli as well as the response to DNA damage, and the disruption of these signal transduction pathways provides an explanation for ataxia-telangiectasia characteristics such as ionizing radiation sensitivity, immunodeficiency, and infertility. Although the first Fanconi anemia gene (FAC) was cloned over 5 years ago, and a second Fanconi anemia gene (FAA) was cloned in 1996, the biochemical function of Fanconi anemia proteins largely remains a mystery. The recent construction of mutant mouse strains for several of these diseases should help unlock the difficult puzzle of the pathogenesis of these syndromes.
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PMID:Disorders of DNA replication and repair. 942 94


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