Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic alcohol abuse has deleterious effects on several organs in the body including the brain. Neuroradiological studies have demonstrated that the brains of chronic alcoholics undergo loss of both gray and white matter volumes. Neuropathological studies using unbiased stereological methods have provided evidence for loss of neurons in specific parts of the brain in chronic alcoholics. The purpose of this paper is to propose a mechanism for this alcohol related neuronal loss. The hypothesis is based on the neurodegeneration observed in patients with the genetic disorder xeroderma pigmentosum (XP), who lack the capacity to carry out a specific type of DNA repair called nucleotide excision repair (NER). Some XP patients develop a progressive atrophic neurodegeneration, termed XP neurological disease, indicating that endogenous DNA damage that is normally repaired by NER has the capacity to cause neuronal death. Accumulating evidence indicates that the neurodegenerative DNA damage that is responsible for neuronal loss in XP patients results from reactive oxygen species (ROS) and lipid peroxidation products, and has the capacity to inhibit gene expression by RNA polymerase II. Therefore, the following model is proposed: chronic alcohol abuse results in increased levels of ROS and lipid peroxidation products in neurons, which results in an overwhelming burden on the NER pathway, and increased steady state levels of DNA lesions that inhibit gene expression. This results in neuronal death either by reduction in the levels of essential gene products or by apoptosis. The implications of this model for future studies are discussed.
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PMID:Brain atrophy and neuronal loss in alcoholism: a role for DNA damage? 1087 92

The p89/xeroderma pigmentosum complementation group B (XPB) ATPase-helicase of transcription factor IIH (TFIIH) is essential for promoter melting prior to transcription initiation by RNA polymerase II (RNAPII). By studying the topological organization of the initiation complex using site-specific protein-DNA photo-cross-linking, we have shown that p89/XPB makes promoter contacts both upstream and downstream of the initiation site. The upstream contact, which is in the region where promoter melting occurs (positions -9 to +2), requires tight DNA wrapping around RNAPII. The addition of hydrolyzable ATP tethers the template strand at positions -5 and +1 to RNAPII subunits. A mutation in p89/XPB found in a xeroderma pigmentosum patient impairs the ability of TFIIH to associate correctly with the complex and thereby melt promoter DNA. A model for open complex formation is proposed.
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PMID:Mechanism of promoter melting by the xeroderma pigmentosum complementation group B helicase of transcription factor IIH revealed by protein-DNA photo-cross-linking. 1102 86

Transcription-coupled repair (TCR) plays an important role in removing DNA damage from actively transcribed genes. It has been speculated that TCR is the most important mechanism for repairing DNA damage in non-dividing cells such as neurons. Therefore, abnormal TCR may contribute to the development of many age-related and neurodegenerative diseases. However, the molecular mechanism of TCR is not well understood. Oligonucleotide DNA triplex formation provides an ideal system to dissect the molecular mechanism of TCR since triplexes can be formed in a sequence-specific manner to inhibit transcription of target genes. We have recently studied the molecular mechanism of triplex-forming oligonucleotide (TFO)-mediated TCR in HeLa nuclear extracts. Using plasmid constructs we demonstrate that the level of TFO-mediated DNA repair activity is directly correlated with the level of transcription of the plasmid in HeLa nuclear extracts. TFO-mediated DNA repair activity was further linked with transcription since the presence of rNTPs in the reaction was essential for AG30-mediated DNA repair activity in HeLa nuclear extracts. The involvement of individual components, including TFIID, TFIIH, RNA polymerase II and xeroderma pigmentosum group A (XPA), in the triplex-mediated TCR process was demonstrated in HeLa nuclear extracts using immunodepletion assays. Importantly, our studies also demonstrated that XPC, a component involved in global genome DNA repair, is involved in the AG30-mediated DNA repair process. The results obtained in this study provide an important new understanding of the molecular mechanisms involved in the TCR process in mammalian cells.
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PMID:Detection and determination of oligonucleotide triplex formation-mediated transcription-coupled DNA repair in HeLa nuclear extracts. 1129 53

TFIIH is a multifunctional RNA polymerase II general initiation factor that includes two DNA helicases encoded by the Xeroderma pigmentosum complementation group B (XPB) and D (XPD) genes and a cyclin-dependent protein kinase encoded by the CDK7 gene. Previous studies have shown that the TFIIH XPB DNA helicase plays critical roles not only in transcription initiation, where it catalyzes ATP-dependent formation of the open complex, but also in efficient promoter escape, where it suppresses arrest of very early RNA polymerase II elongation intermediates. In this report, we present evidence that ATP-dependent TFIIH action in transcription initiation and promoter escape requires distinct regions of the DNA template; these regions are well separated from the promoter region unwound by the XPB DNA helicase and extend, respectively, approximately 23-39 and approximately 39-50 bp downstream from the transcriptional start site. Taken together, our findings bring to light a role for promoter DNA in TFIIH action and are consistent with the model that TFIIH translocates along promoter DNA ahead of the RNA polymerase II elongation complex until polymerase has escaped the promoter.
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PMID:TFIIH action in transcription initiation and promoter escape requires distinct regions of downstream promoter DNA. 1133 64

The XPD gene is required for excision repair of UV-damaged DNA and is an important component of nucleotide excision repair (NER). Mutations in the XPD gene generate the cancer-prone syndrome xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy. XPD is a component of the TFIIH transcription factor, which is essential for RNA polymerase II elongation. In this work, we report the construction of transgenic flies overexpressing the antisense RNA of the Drosophila melanogaster XPD homolog (DmXPD). These flies show an increased sensitivity to UV radiation compared with the wild-type. This is an expected phenotype if the XPD function is affected and indicates that the antisense approach may be an alternative in the study of TFIIH functions in Drosophila.
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PMID:Increased UV light sensitivity in transgenic Drosophila expressing the antisense XPD homolog. 1133 41

The skin-cancer-prone hereditary disease xeroderma pigmentosum is typically characterized by defective nucleotide excision repair (NER) of DNA. However, since all subunits of the core basal transcription factor TFIIH are required for both RNA polymerase II basal transcription and NER, some mutations affecting genes that encode TFIIH subunits can result in clinical phenotypes associated with defective basal transcription. Among these is a syndrome called trichothiodystrophy (TTD) in which the prominent features are brittle hair and nails, and dry scaly skin. A recent study provides dramatic support for the so-called transcription hypothesis of TTD.(1) Specifically, several patients have been shown to carry a mutation in the XPD gene, which encodes a thermolabile form of XPD protein, resulting in loss of hair during febrile episodes.
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PMID:Hot news: temperature-sensitive humans explain hereditary disease. 1149 13

To understand the relationship between DNA repair, apoptosis, transcription, and cancer-proneness, we have studied the apoptotic response and the recovery of RNA synthesis following ultraviolet C and ultraviolet B irradiation in nucleotide excision repair deficient diploid fibroblasts from the cancer-prone xeroderma pigmentosum (XP) syndrome patients and the non-cancer-prone trichothiodystrophy (TTD) patients. Analysis of four XPD and four TTD/XPD fibroblast strains presenting different mutations on the XPD gene has shown that XPD cells are more sensitive to ultraviolet-induced apoptosis than TTD/XPD cells, and this response seems to be modulated by the type and the location of the mutation on the XPD gene. Moreover, the other xeroderma pigmentosum fibroblast strains analyzed (groups A and C) are more sensitive to undergo apoptosis after ultraviolet irradiation than normal human fibroblasts, showing that the cancer-proneness of xeroderma pigmentosum patients is not due to a deficiency in the ultraviolet-induced apoptotic response. We have also found that cells from transcription-coupled repair deficient XPA, XPD, TTD/XPD, and Cockayne's syndrome patients undergo apoptosis at lower ultraviolet doses than transcription-coupled repair proficient cells (normal human fibroblasts and XPC), indicating that blockage of RNA polymerase II at unrepaired lesions on the transcribed strand is the trigger. Moreover, XPD and XPA cells are more sensitive to ultraviolet-induced apoptosis than trichothiodystrophy and Cockayne's syndrome fibroblasts, suggesting that both cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone on the transcribed strand trigger apoptosis. Finally, we show that apoptosis is directly proportional to the level of inhibition of transcription, which depends on the density of ultraviolet-induced lesions occurring on transcribed sequences.
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PMID:Effects of XPD mutations on ultraviolet-induced apoptosis in relation to skin cancer-proneness in repair-deficient syndromes. 1171 Sep 28

In addition to xeroderma pigmentosum, mutations in the human XPG gene cause early onset Cockayne syndrome (CS). Here, we provide evidence for the involvement of RAD2, the S. cerevisiae counterpart of XPG, in promoting efficient RNA polymerase II transcription. Inactivation of RAD26, the S. cerevisiae counterpart of the human CSB gene, also causes a deficiency in transcription, and a synergistic decline in transcription occurs in the absence of both the RAD2 and RAD26 genes. Growth is also retarded in the rad2 Delta and rad26 Delta single mutant strains, and a very severe growth inhibition is seen in the rad2 Delta rad26 Delta double mutant. From these and other observations presented here, we suggest that transcriptional defects are the underlying cause of CS.
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PMID:Requirement of yeast RAD2, a homolog of human XPG gene, for efficient RNA polymerase II transcription. implications for Cockayne syndrome. 1211 Jan 80

UV radiation induces DNA lesions that are repaired by the nucleotide excision repair (NER) pathway. Cells that are NER deficient such as those derived from xeroderma pigmentosum (XP) patients are susceptible to apoptosis after 10J/m(2) UV radiation, a dose largely survivable by repair proficient cells. Herein, we report that RNA polymerase II large subunit (RNAP II-LS) undergoes caspase-mediated cleavage, yielding a 140kDa C-terminal fragment in XP lymphoblasts but not NER proficient lymphoblasts after 10J/m(2) UV irradiation. Cleavage could also be induced by cisplatin or oxaliplatin, but not transplatin, an isomer of cisplatin that does not induce DNA adducts. The cleavage of RNAP II-LS was blocked by a panel of caspase inhibitors but not by proteasomal inhibitors or inhibitors of other proteases. In vitro cleavage with caspase 8 yielded the same 140kDa RNAP II-LS fragment observed in vivo. Using site-directed mutagenesis, the RNAP II-LS cleavage site was localized to an LETD sequence ending at residue 1339, which is near its C-terminal domain.
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PMID:RNA polymerase II large subunit is cleaved by caspases during DNA damage-induced apoptosis. 1220 Jan 41

The hepatocarcinogen 2-acetylaminofluorene is one of the most studied experimental carcinogens. We have shown previously that normal rat hepatocytes accumulate the tumour suppressor p53 after exposure to this compound while preneoplastic rat hepatocytes do not. We suggested that the lack of p53 response may confer a growth advantage on preneoplastic hepatocytes and may be an important factor in hepatic tumor promotion by 2-acetylaminofluorene and other genotoxic compounds. Inhibition of RNA polymerase II driven transcription by DNA lesions may constitute one of the mechanisms leading to accumulation of the tumour suppressor p53. We have investigated the accumulation of p53 by structurally different DNA lesions of 2-acetylaminofluorene for which the rate of nucleotide excision repair (NER) and inhibition of transcription are known. Experiments were performed with NER proficient human fibroblasts as well as repair deficient xeroderma pigmentosum group A (XPA) cells, XPC cells [only transcription coupled repair (TCR)] and Cockayne syndrome (CS)B cells [only global genome repair (GGR)]. The cells were exposed to N-acetoxy-acetylaminofluorene (NAAAF) in the presence or absence of paraoxon inducing dG-C8-AAF or dG-C8-AF adducts respectively. Both treatments led to accumulation of p53 in all cells. However, dG-C8-AAF adducts produced greater p53 induction than dG-C8-AF adducts. The percentage p53-positive cells was highest and the threshold for p53 accumulation was lowest in XPA and CSB cells. Our results further demonstrate that both the potency of a lesion to inhibit transcription as well as the restoration of RNA synthesis determines the magnitude of p53 induction.
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PMID:Blockage of transcription as a trigger for p53 accumulation by 2-acetylaminofluorene DNA-adducts. 1288 15


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