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)

Nucleotide excision repair (NER) is a versatile repair pathway to remove a variety of DNA distorting lesions. NER operate via two subpathways, that are global genome repair (GGR) and transcription coupled nucleotide excision repair (TCR). GGR removes DNA damage from the genome over all, whilst TCR is selectively directed to DNA lesions in the transcribed strand of expressed genes. The damage recognition step in GGR and TCR is also different. In GGR, the XPC-HR23B complex is an essential factor to recruit proteins for subsequent process. In TCR, a stalled RNA polymerase II is a presumed trigger to initiate TCR machinery in concert with Cockayne syndrome (CS) proteins. Mismatch repair (MMR) keeps fidelity of DNA replication through correcting replication errors. A distinctive feature of MMR pathway is that this repair is directed exclusively to the newly synthesized strand. This characteristic contributes to mediation of cytotoxity by methylating agents, and MMR deficient cells are more resistant to methylating agents than MMR proficient cells. The interaction between MMR and NER has been reported by several investigators. However, the most controversial problem is the role of MMR in TCR TCR in E. coli requires the participation of the MutS and MutL MMR proteins. On the contrary, TCR in yeast is independent of the yeast MutS and MutL homologues. To date, in mammalian cells, there are conflicting evidences for the association of MMR with TCR pathway. The aim of this article is to provide a brief overview of the recent literature on this subject.
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PMID:Involvement of mismatch repair in transcription-coupled nucleotide excision repair. 1702 43

Rpb9, a small nonessential subunit of RNA polymerase II, has been shown to have multiple transcription-related functions in Saccharomyces cerevisiae. These functions include promoting transcription elongation and mediating a subpathway of transcription-coupled repair (TCR) that is independent of Rad26, the homologue of human Cockayne syndrome complementation group B protein. Rpb9 is composed of three distinct domains: the N-terminal Zn1, the C-terminal Zn2, and the central linker. Here we show that the Zn1 and linker domains are essential, whereas the Zn2 domain is almost dispensable, for both transcription elongation and TCR functions. Impairment of transcription elongation, which does not dramatically compromise Rad26-mediated TCR, completely abolishes Rpb9-mediated TCR. Furthermore, Rpb9 appears to be dispensable for TCR if its transcription elongation function is compensated for by removing a transcription repression/elongation factor. Our data suggest that the transcription elongation function of Rpb9 is involved in TCR.
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PMID:Evidence that the transcription elongation function of Rpb9 is involved in transcription-coupled DNA repair in Saccharomyces cerevisiae. 1703 Jun 4

Eukaryotic cells respond to a variety of DNA insults by triggering a common signal transduction cascade, known as checkpoint response, which temporarily halts cell-cycle progression. Although the main players involved in the cascade have been identified, there is still uncertainty about the nature of the structures that activate these surveillance mechanisms. To understand the role of nucleotide excision repair (NER) in checkpoint activation, we analyzed the UV-induced phosphorylation of the key checkpoint proteins Chk1 and p53, in primary fibroblasts from patients with xeroderma pigmentosum (XP), Cockayne syndrome (CS), trichothiodystrophy (TTD), or UV light-sensitive syndrome. These disorders are due to defects in transcription-coupled NER (TC-NER) and/or global genome NER (GG-NER), the NER subpathways repairing the transcribed strand of active genes or the rest of the genome, respectively. We show here that in G0/G1 and G2/M phases of the cell cycle, triggering of the DNA damage cascade requires recognition and processing of the lesions by the GG-NER. Loss of TC-NER does not affect checkpoint activation. Mutations in XPD, XPB, and in TTDA, encoding subunits of the TFIIH complex, involved in both transcription and NER, impair checkpoint triggering. The only exception is represented by mutations in XPD, resulting in combined features of XP and CS (XP/CS) that lead to activation of the checkpoint cascade after UV radiation. Inhibition of RNA polymerase II transcription significantly reduces the phosphorylation of key checkpoint factors in XP/CS fibroblasts on exposure to UV damage.
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PMID:DNA nucleotide excision repair-dependent signaling to checkpoint activation. 1708 60

Transcription-coupled repair (TCR) is a sub-pathway of nucleotide excision repair (NER) able to remove bulky DNA lesions located on the transcribed strands of active genes more rapidly than those located on the non-transcribed genomic DNA. Two recently published reports try to dissect the molecular mechanisms of TCR using simplified in vitro assays. A third report shows in vivo data that confirmed the in vitro ones and extends them to the role of other TCR factors such as those involved in chromatin remodeling. These approaches shed light on the interplay between stalled RNA polymerase II and NER factors necessary for efficient repair. Because severe diseases, such as Cockayne syndrome, are associated with defects or mutations in proteins required for transcription-coupled nucleotide excision repair, complete understanding of this pathway should allow us to understand this disease better and eventually to propose adequate therapies.
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PMID:New insights for understanding the transcription-coupled repair pathway. 1719 29

The Cockayne syndrome B protein (CSB) has long been known to be involved in the repair of DNA modifications that block the RNA polymerase in transcribed DNA sequences (transcription-coupled repair). Recent evidence suggests that it also has a more general role in the repair of oxidative DNA base modifications such as 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxoG). In mammalian cells, 8-oxoG is a substrate of the repair glycosylase OGG1. Mice without this enzyme accumulate 8-oxoG in the genome and have elevated spontaneous mutation rates. To elucidate the role of CSB in the prevention of mutations by oxidative DNA base damage, we have generated mice that are deficient in Csb or Ogg1 or both genes and carry a non-transcribed bacterial lacI gene for mutation analysis (Big Blue mice). Our results indicate that the overall spontaneous mutation frequencies in the livers of Csb(m/m)/Ogg1-/- -mice are elevated not only compared with heterozygous control mice (factor 3.3), but also with Ogg1-/- -animals (factor 1.6). Sequence analysis revealed that the additional mutations caused by CSB deficiency in an Ogg1-/- background are mostly G:C to T:A transversions and small deletions. For all mouse strains, the background levels of oxidative purine modifications in the livers correlate linearly with the numbers of G:C to T:A transversions observed. The data indicate that CSB is involved in the inhibition of mutations caused by spontaneous oxidative DNA base damage in a non-transcribed gene.
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PMID:Deficiency of the Cockayne syndrome B (CSB) gene aggravates the genomic instability caused by endogenous oxidative DNA base damage in mice. 1721 18

Transcription-coupled repair (TCR) efficiently removes a variety of lesions from the transcribed strand of active genes. Mutations in Cockayne syndrome group A and B genes (CSA and CSB) result in defective TCR, but the molecular mechanism of TCR in mammalian cells is not clear. We have found that CSA protein is translocated to the nuclear matrix after UV irradiation and colocalized with the hyperphosphorylated form of RNA polymerase II and that the translocation is dependent on CSB. We developed a cell-free system for the UV-induced translocation of CSA. A cytoskeleton (CSK) buffer-soluble fraction containing CSA and a CSK buffer-insoluble fraction prepared from UV-irradiated CS-A cells were mixed. After incubation, the insoluble fraction was treated with DNase I. CSA protein was detected in the DNase I-insoluble fraction, indicating that it was translocated to the nuclear matrix. In this cell-free system, the translocation was dependent on UV irradiation, CSB function, and TCR-competent CSA. Moreover, the translocation was dependent on functional TFIIH, as well as chromatin structure and transcription elongation. These results suggest that alterations of chromatin at the RNA polymerase II stall site, which depend on CSB and TFIIH at least, are necessary for the UV-induced translocation of CSA to the nuclear matrix.
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PMID:Functional TFIIH is required for UV-induced translocation of CSA to the nuclear matrix. 1724 93

Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2) is composed of 855 amino acids, contains 15 tetratricopeptide repeat motifs, and associates with Cockayne syndrome group A and B proteins and RNA polymerase II, as well as XPA. In vitro and in vivo studies showed that XAB2 is involved in pre-mRNA splicing, transcription, and transcription-coupled DNA repair, leading to preimplantation lethality, and is essential for mouse embryogenesis. Retinoids are effective for the treatment of preneoplastic diseases including xeroderma pigmentosum and other dermatologic diseases such as photoaging. We therefore focused on defining the effect of XAB2 on cellular differentiation in the presence of ATRA treatment. In the present study, we showed that overexpression of XAB2 inhibited ATRA-induced cellular differentiation in human rhabdomyosarcoma cell line, and that knockdown of XAB2 by small interfering RNA (siRNA) increased ATRA-sensitive cellular differentiation in the human promyelocytic leukemia cell line HL60 at both physiologic (10(-9)-10(-8) mol/L) and therapeutic (10(-7) mol/L) concentrations of ATRA. Moreover, we found that XAB2 was associated with retinoic acid receptor alpha (RARalpha) and histone deacetylase 3 in the nuclei. Finally, using siRNA against XAB2, we showed that the ATRA-resistant neuroblastoma cell line IMR-32 underwent cellular differentiation induced by ATRA at a therapeutic concentration (10(-6) mol/L). These results strongly suggest that XAB2 is a component of the RAR corepressor complex with an inhibitory effect on ATRA-induced cellular differentiation and that XAB2 plays a role in ATRA-mediated cellular differentiation as an important aspect of cancer therapy.
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PMID:Knockdown of XAB2 enhances all-trans retinoic acid-induced cellular differentiation in all-trans retinoic acid-sensitive and -resistant cancer cells. 1728 34

Here, we characterize the mutant transcripts resulting from bypass of an 8,5'-cyclo-2'-deoxyadenosine (cyclo-dA) or cyclobutane pyrimidine dimer (CPD) by human RNA polymerase II (Pol II) in vivo. With the cyclo-dA lesion, we observed two new types of mutant transcripts. In the first type, the polymerase inserted uridine opposite the lesion and then misincorporated adenosine opposite the template deoxyadenosine downstream (5') of the lesion. The second type contained deletions of 7, 13 or 21 nucleotides (nt) after uridine incorporation opposite the lesion. The frequency of the different types of transcript from the cyclo-dA lesion in mutant human cell lines suggests that the Cockayne syndrome B protein affects the probability of deletion transcript formation. With the CPD-containing construct, we also detected rare transcripts containing 12 nt deletions. These results indicate that RNA pol II in living human cells can bypass helix-distorting DNA lesions that are substrates for nucleotide excision repair, resulting in transcriptional mutagenesis.
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PMID:Transcriptional bypass of bulky DNA lesions causes new mutant RNA transcripts in human cells. 1736 72

Cockayne syndrome group B (CSB) protein plays a role in both transcription-coupled DNA repair and transcriptional regulation of all three classes of nuclear RNA polymerases. Here we show that a complex consisting of CSB, RNA polymerase I (Pol I), and histone methyltransferase G9a is present at active rRNA genes. G9a methylates histone H3 on lysine 9 (H3K9me2) in the pre-rRNA coding region and facilitates the association of heterochromatin protein 1gamma (HP1gamma) with rDNA. Both H3K9 methylation and HP1gamma association require ongoing transcription. Knockdown of CSB prevents the association of Pol I with rDNA, impairs the interaction of G9a with Pol I, and inhibits pre-rRNA synthesis. Likewise, knockdown of G9a leads to decreased levels of H3K9me2 in the transcribed region and downregulation of pre-rRNA synthesis. The results reveal the mechanism underlying CSB-mediated activation of rDNA transcription and link G9a-dependent H3K9 methylation to Pol I transcription elongation through chromatin.
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PMID:Activation of RNA polymerase I transcription by cockayne syndrome group B protein and histone methyltransferase G9a. 1770 30

Nucleotide excision repair is a versatile repair pathway that counteracts the deleterious effects of various DNA lesions. In nucleotide excision repair, there is a transcription-coupled repair (TCR) pathway that focuses on DNA damage that blocks RNA polymerase IIo in transcription elongation. XAB2 (XPA-binding protein 2), containing tetratricopeptide repeats, has been isolated by virtue of its ability to interact with xeroderma pigmentosum group A protein (XPA). Moreover, XAB2 has been shown to interact with Cockayne syndrome group A and B proteins (CSA and CSB) and RNA polymerase II, as well as XPA, and is involved in TCR and transcription. Here we purified XAB2 as a multimeric protein complex consisting of hAquarius, XAB2, hPRP19, CCDC16, hISY1, and PPIE, which are involved in pre-mRNA splicing. Knockdown of XAB2 with small interfering RNA in HeLa cells resulted in a hypersensitivity to killing by UV light and a decreased recovery of RNA synthesis after UV irradiation and regular RNA synthesis. Enhanced interaction of XAB2 with RNA polymerase IIo or XPA was observed in cells treated with DNA-damaging agents, indicating DNA damage-responsive activity of the XAB2 complex. These results indicated that the XAB2 complex is a multifunctional factor involved in pre-mRNA splicing, transcription, and TCR.
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PMID:Isolation of XAB2 complex involved in pre-mRNA splicing, transcription, and transcription-coupled repair. 1798 4


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