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)

Transcription-coupled repair (TCR) efficiently removes a variety of lesions from the transcribed strand of active genes. By allowing rapid resumption of RNA synthesis, the process is of major importance for cellular resistance to transcription-blocking genotoxic damage. Mutations in the Cockayne syndrome group A or B (CSA or CSB) gene result in defective TCR. However, the exact mechanism of TCR in mammalian cells remains to be elucidated. We found that CSA protein is rapidly translocated to the nuclear matrix after UV irradiation. The translocation of CSA was independent of Xeroderma pigmentosum group C, which is specific to the global genome repair subpathway of nucleotide excision repair (NER) and of the core NER factor Xeroderma pigmentosum group A but required the CSB protein. In UV-irradiated cells, CSA protein colocalized with the hyperphosphorylated form of RNA polymerase II, engaged in transcription elongation. The translocation of CSA was also induced by treatment of the cells with cisplatin or hydrogen peroxide, both of which produce damage that is subjected to TCR but not induced by treatment with dimethyl sulfate, which produces damage that is not subjected to TCR. The hydrogen peroxide-induced translocation of CSA was also CSB dependent. These findings establish a link between TCR and the nuclear matrix mediated by CSA.
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PMID:Translocation of Cockayne syndrome group A protein to the nuclear matrix: possible relevance to transcription-coupled DNA repair. 1178 47

Eukaryotic cells use multiple, highly conserved mechanisms to contend with ultraviolet-light-induced DNA damage. One important response mechanism is transcription-coupled repair (TCR), during which DNA lesions in the transcribed strand of an active gene are repaired much faster than in the genome overall. In mammalian cells, defective TCR gives rise to the severe human disorder Cockayne's syndrome (CS). The best-studied CS gene, CSB, codes for a Swi/Snf-like DNA-dependent ATPase, whose yeast homologue is called Rad26 (ref. 4). Here we identify a yeast protein, termed Def1, which forms a complex with Rad26 in chromatin. The phenotypes of cells lacking DEF1 are consistent with a role for this factor in the DNA damage response, but Def1 is not required for TCR. Rather, def1 cells are compromised for transcript elongation, and are unable to degrade RNA polymerase II (RNAPII) in response to DNA damage. Our data suggest that RNAPII stalled at a DNA lesion triggers a coordinated rescue mechanism that requires the Rad26-Def1 complex, and that Def1 enables ubiquitination and proteolysis of RNAPII when the lesion cannot be rapidly removed by Rad26-promoted DNA repair.
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PMID:A Rad26-Def1 complex coordinates repair and RNA pol II proteolysis in response to DNA damage. 1185 74

Transcription-coupled repair (TCR) is essential for the rapid, preferential removal of DNA damage in active genes. The large subunit of RNA polymerase (Pol) II is ubiquitinated in cells after UV-irradiation or cisplatin treatment, which induces DNA damage preferentially repaired by TCR. Several human mutations, such as Cockayne syndrome complementation groups A and B, are defective in TCR and incapable of Pol II ubiquitination upon DNA damage. Here we demonstrate a correlation between ubiquitination of RNA Pol II and arrest of transcription in vitro. Ubiquitination of Pol II is significantly induced by alpha-amanitin, an amatoxin that blocks Pol II elongation and causes its degradation in cells. Pol II undergoes similar ubiquitination on DNA containing cisplatin adducts that arrest transcription. Stimulation of ubiquitination requires the addition of template DNA and does not occur in the presence of an antibody to the general transcription factor TFIIB, indicating the transcription dependence of the reaction. We propose that components of the reaction recognize elongating Pol II-DNA complexes arrested by alpha-amanitin or cisplatin lesions, triggering ubiquitination.
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PMID:Transcription-coupled and DNA damage-dependent ubiquitination of RNA polymerase II in vitro. 1190 82

RAD26 in the yeast Saccharomyces cerevisiae is the counterpart of the human Cockayne syndrome group B (CSB) gene. Both RAD26 and CSB act in the preferential repair of UV lesions on the transcribed strand, and in this process, they function together with the components of nucleotide excision repair (NER). Here, we examine the role of RAD26 in the repair of DNA lesions induced upon treatment with the alkylating agent methyl methanesulfonate (MMS). MMS-induced DNA lesions include base damages such as 3-methyl adenine and 7-methyl guanine, and these lesions are removed in yeast by the alternate competing pathways of base excision repair (BER), which is initiated by the action of MAG1-encoded N-methyl purine DNA glycosylase, and NER. Interestingly, a synergistic increase in MMS sensitivity was observed in the rad26 Delta strain upon inactivation of NER or BER, indicating that RAD26 promotes the survival of MMS-treated cells by a mechanism that acts independently of either of these repair pathways. The galactose-inducible transcription of the GAL2, GAL7, and GAL10 genes is reduced in MMS-treated rad26 Delta cells and also in mag1 Delta rad14 Delta cells, whereas a very severe reduction in transcription occurs in MMS-treated mag1 Delta rad14 Delta rad26 Delta cells. From these observations, we infer that RAD26 plays a role in promoting transcription by RNA polymerase II through damaged bases. The implications of these observations are discussed in this paper.
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PMID:Yeast RAD26, a homolog of the human CSB gene, functions independently of nucleotide excision repair and base excision repair in promoting transcription through damaged bases. 1202 48

The ubiquitous process of nucleotide excision repair includes an obligatory step of DNA repair synthesis (DRS) to fill the gapped heteroduplex following excision of a short (approximately 30-nucleotide) damaged single-strand fragment. Using 5-iododeoxyuridine to label repair patches during the first 10-60 min after UV irradiation of quiescent normal human fibroblasts we have visualized a limited number of discrete foci of DRS. These must reflect clusters of elementary DRS patches, since single patches would not be detected. The DRS foci are attenuated in normal cells treated with alpha-amanitin or in Cockayne syndrome (CS) cells, which are specifically deficient in the pathway of transcription-coupled repair (TCR). It is therefore likely that the clusters of DRS arise in chromatin domains within which RNA polymerase II transcription is compartmentalized. However, we also found significant suppression of DRS foci in xeroderma pigmentosum, complementation group C cells in which global genome repair (GGR) is defective, but TCR is normal. This suggests that the TCR is responsible for the DRS cluster formation in the absence of GGR. The residual foci detected in CS cells indicate that, even at early times following UV irradiation, GGR may open some chromatin domains for processive scanning and consequent DRS independent of transcription.
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PMID:Clustered sites of DNA repair synthesis during early nucleotide excision repair in ultraviolet light-irradiated quiescent human fibroblasts. 1202 58

Cockayne syndrome (CS) is an autosomal recessive human disease characterized by UV-sensitivity as well as neurological and developmental abnormalities. Two complementation groups have been established, designated CS-A and CS-B. Traditionally, CSA and CSB have been ascribed a function in the transcription-coupled repair (TCR) pathway of nucleotide excision repair (NER) that efficiently removes bulky lesions from the transcribed strand of RNA polymerase II transcribed genes. To assess the role of the CSB protein in the repair of the highly mutagenic base lesion 7,8-dihydro-8-oxoguanine (8-oxoG), we have investigated the removal of this lesion using an in vitro incision approach with cell extracts as well as an in vivo approach with a modified protocol of the gene-specific repair assay, which allows the measurement of base lesion repair in intragenomic sequences. Our results demonstrate that the integrity of the CSB protein is pivotal for processes leading to incision at the site of 8-oxoG and that the global genome repair (GGR) of this lesion requires a functional CSB gene product in vivo.
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PMID:Global genome repair of 8-oxoG in hamster cells requires a functional CSB gene product. 1203 59

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

Previously, we found that Rad26, the yeast Cockayne syndrome B homolog and the transcription elongation factor Spt4 mediate transcription-coupled repair of UV-induced DNA damage. Here we studied the effect of DNA damage on transcription by directly analyzing the RNA polymerase II localization at active genes in vivo. A rad26 defect leads to loss of Ser5 phosphorylated RNA polymerase II localization to active genes, while localization is only transiently diminished in wild type cells. In contrast, loss of Ser5-P RNAP II localization is suppressed in spt4 cells. Interestingly, even when DNA damage is persistent the absence of Spt4 leads to a delayed loss of transcription suggesting that Spt4 is directly involved in mediating transcription shutdown. Comparative analysis of phosphorylated and non-phosphorylated RNA polymerase II localization revealed that Ser5-P RNAP II is preferentially lost in the presence of DNA damage. In addition, we found evidence for a transient Rad26 localization to active genes in response to DNA damage. These findings provide insight into the transcriptional response to DNA damage and the factors involved in communicating this response, which has direct implications for our understanding of transcription-repair coupling.
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PMID:Transcription elongation factor Spt4 mediates loss of phosphorylated RNA polymerase II transcription in response to DNA damage. 1217 94

The severe hereditary progeroid disorder Cockayne syndrome is a consequence of a defective transcription-coupled repair (TCR) pathway. This special mode of DNA repair aids a RNA polymerase that is stalled by a DNA lesion in the template and ensures efficient DNA repair to permit resumption of transcription and prevent cell death. Although some key players in TCR, such as the Cockayne syndrome A (CSA) and B (CSB) proteins have been identified, the exact molecular mechanism still remains illusive. A recent report provides new unexpected insights into TCR in yeast. The identification and characterisation of a novel protein co-purifying with the yeast homologue of CSB (Rad26) imposes reassessment of our current understanding of TCR in yeast. What about humans?
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PMID:When machines get stuck--obstructed RNA polymerase II: displacement, degradation or suicide. 1221 May 13

Abasic (AP) sites represent one of the most frequently formed lesions in DNA. Here, we examine the consequences of the stalling of RNA polymerase II at AP sites in DNA in Saccharomyces cerevisiae. A severe inhibition of transcription occurs in strains that are defective in the removal of AP sites and that also lack the RAD26 gene, a homolog of the human Cockayne syndrome group B (CSB) gene, and, importantly, a dramatic rise in mutagenesis is incurred in such strains. From the various observations presented here, we infer that the stalling of transcription at AP sites is highly mutagenic.
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PMID:The stalling of transcription at abasic sites is highly mutagenic. 1248 89


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