Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The XAB2 protein (XPA-binding protein 2) with 15 tetratricopeptide repeat motifs has been isolated by virtue of its ability to interact with xeroderma pigmentosum group A (XPA) protein in the yeast two-hybrid system. It has been shown that XAB2 interacted with Cockayne syndrome groups A and B (CSA and CSB) proteins and RNA polymerase II, which are known to be involved in transcription-coupled repair (TCR) and transcription, and that the antibodies against XAB2 protein inhibited the recovery of RNA synthesis after UV irradiation and normal RNA synthesis when microinjected into living fibroblasts. These results have indicated that XAB2 is involved in TCR and transcription. In this report, to elucidate the function of XAB2 in vivo, two types of mutations were introduced into the XAB2 gene in mice: a deletion of the region encompassing the promoter and exons 1-4, and a deletion of the C-terminal 162 amino acids. Both types of XAB2-heterozygous mice appeared normal physiologically and behaviorally. However, XAB2-homozygotes were selectively absent among the newborn mice. A detailed analysis of embryos at different stages of development indicated that the XAB2-homozygous mutants could survive until the morula stage, but could not develop to the blastocyst stage. These results indicate that XAB2 has an essential function in mouse embryogenesis.
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PMID:Disruption of mouse XAB2 gene involved in pre-mRNA splicing, transcription and transcription-coupled DNA repair results in preimplantation lethality. 1572 28

Loss of a nonenzymatic function of XPG results in defective transcription-coupled repair (TCR), Cockayne syndrome (CS), and early death, but the molecular basis for these phenotypes is unknown. Mutation of CSB, CSA, or the TFIIH helicases XPB and XPD can also cause defective TCR and CS. We show that XPG interacts with elongating RNA polymerase II (RNAPII) in the cell and binds stalled RNAPII ternary complexes in vitro both independently and cooperatively with CSB. XPG binds transcription-sized DNA bubbles through two domains not required for incision and functionally interacts with CSB on these bubbles to stimulate its ATPase activity. Bound RNAPII blocks bubble incision by XPG, but an ATP hydrolysis-dependent process involving TFIIH creates access to the junction, allowing incision. Together, these results implicate coordinated recognition of stalled transcription by XPG and CSB in TCR initiation and suggest that TFIIH-dependent remodeling of stalled RNAPII without release may be sufficient to allow repair.
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PMID:Recognition of RNA polymerase II and transcription bubbles by XPG, CSB, and TFIIH: insights for transcription-coupled repair and Cockayne Syndrome. 1624 22

The WSTF (Williams syndrome transcription factor) protein is involved in vitamin D-mediated transcription and replication as a component of two distinct ATP-dependent chromatin remodeling complexes, WINAC and WICH, respectively. We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. B-WICH also contains RNAs, 45 S rRNA, 5 S rRNA, 7SL RNA, and traces of the U2 small nuclear RNA. The core proteins, WSTF, SNF2h, and nuclear myosin 1, are associated with the RNA polymerase III genes 5 S rRNA genes and 7SL, and post-transcriptional silencing of WSTF reduces the levels of these transcripts. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling.
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PMID:The WSTF-SNF2h chromatin remodeling complex interacts with several nuclear proteins in transcription. 1660 71

Restoration of UV-inhibited transcription requires removal of transcription-blocking DNA lesions by transcription-coupled repair (TCR). In mammals, TCR is dependent on CSA and CSB proteins; however, their functions are largely unknown. Here, we analyzed the composition of UV-stalled transcription elongation complexes from human cells. We show that CSB and CSA display differential roles in recruitment of TCR-specific factors and that assembly for TCR occurs without disruption of the UV-stalled RNA polymerase II (RNAPIIo). CSB fulfills a key role as a coupling factor to attract histone acetyltransferase p300, nucleotide excision repair (NER) proteins, and CSA-DDB1 E3-ubiquitin ligase complex with the COP9 signalosome. CSA is dispensable for attraction of NER proteins to lesion-stalled RNAPIIo, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1, and TFIIS. These results give insight into the nature and order of molecular events that take place during TCR in the context of chromosomal DNA.
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PMID:Cockayne syndrome A and B proteins differentially regulate recruitment of chromatin remodeling and repair factors to stalled RNA polymerase II in vivo. 1691 36

Oxidative lesions represent the most abundant DNA lesions within the cell. In the present study, we investigated the impact of the oxidative lesions 8-oxoguanine, thymine glycol and 5-hydroxyuracil on RNA polymerase II (RNA pol II) transcription using a well-defined in vitro transcription system. We found that in a purified, reconstituted transcription system, these lesions block elongation by RNA pol II to different extents, depending on the type of lesion. Suggesting the presence of a bypass activity, the block to elongation is alleviated when transcription is carried out in HeLa cell nuclear extracts. By purifying this activity, we discovered that TFIIF could promote elongation through a thymine glycol lesion. The elongation factors Elongin and CSB, but not TFIIS, can also stimulate bypass of thymine glycol lesions, whereas Elongin, CSB and TFIIS can all enhance bypass of an 8-oxoguanine lesion. By increasing the efficiency with which RNA pol II reads through oxidative lesions, elongation factors can contribute to transcriptional mutagenesis, an activity that could have implications for the generation or progression of human diseases.
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PMID:RNA polymerase II bypass of oxidative DNA damage is regulated by transcription elongation factors. 1711 Sep 32

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

Expansions of CAG repeat tracts in the germ line underlie several neurological diseases. In human patients and mouse models, CAG repeat tracts display an ongoing instability in neurons, which may exacerbate disease symptoms. It is unclear how repeats are destabilized in nondividing cells, but it cannot involve DNA replication. We showed previously that transcription through CAG repeats induces their instability (Y. Lin, V. Dion, and J. H. Wilson, Nat. Struct. Mol. Biol. 13:179-180). Here, we present a genetic analysis of the link between transcription-induced repeat instability and nucleotide excision repair (NER) in human cells. We show that short interfering RNA-mediated knockdown of CSB, a component specifically required for transcription-coupled NER (TC-NER), and knockdowns of ERCC1 and XPG, which incise DNA adjacent to damage, stabilize CAG repeat tracts. These results suggest that TC-NER is involved in the pathway for transcription-induced CAG repeat instability. In contrast, knockdowns of OGG1 and APEX1, key components involved in base excision repair, did not affect repeat instability. In addition, repeats are stabilized by knockdown of transcription factor IIS, consistent with a requirement for RNA polymerase II (RNAPII) to backtrack from a transcription block. Repeats also are stabilized by knockdown of either BRCA1 or BARD1, which together function as an E3 ligase that can ubiquitinate arrested RNAPII. Treatment with the proteasome inhibitor MG132, which stabilizes repeats, confirms proteasome involvement. We integrate these observations into a tentative pathway for transcription-induced CAG repeat instability that can account for the contractions observed here and potentially for the contractions and expansions seen with human diseases.
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PMID:Transcription-induced CAG repeat contraction in human cells is mediated in part by transcription-coupled nucleotide excision repair. 1759 97

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

The encounter of elongating RNA polymerase II (RNAPIIo) with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract prolonged blockage of transcription, the cell removes the RNAPIIo-blocking DNA lesions by transcription-coupled repair (TC-NER), a specialized subpathway of nucleotide excision repair (NER). Exposure of mice to UVB light or chemicals has elucidated that TC-NER is a critical survival pathway protecting against acute toxic and long-term effects (cancer) of genotoxic exposure. Deficiency in TC-NER is associated with mutations in the CSA and CSB genes giving rise to the rare human disorder Cockayne syndrome (CS). Recent data suggest that CSA and CSB play differential roles in mammalian TC-NER: CSB as a repair coupling factor to attract NER proteins, chromatin remodellers and the CSA- E3-ubiquitin ligase complex to the stalled RNAPIIo. CSA is dispensable for attraction of NER proteins, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1 and TFIIS. The emerging picture of TC-NER is complex: repair of transcription-blocking lesions occurs without displacement of the DNA damage-stalled RNAPIIo, and requires at least two essential assembly factors (CSA and CSB), the core NER factors (except for XPC-RAD23B), and TC-NER specific factors. These and yet unidentified proteins will accomplish not only efficient repair of transcription-blocking lesions, but are also likely to contribute to DNA damage signalling events.
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PMID:Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects. 1816 77

Upon gene activation, we found that RNA polymerase II transcription machinery assembles sequentially with the nucleotide excision repair (NER) factors at the promoter. This recruitment occurs in absence of exogenous genotoxic attack, is sensitive to transcription inhibitors, and depends on the XPC protein. The presence of these repair proteins at the promoter of activated genes is necessary in order to achieve optimal DNA demethylation and histone posttranslational modifications (H3K4/H3K9 methylation, H3K9/14 acetylation) and thus efficient RNA synthesis. Deficiencies in some NER factors impede the recruitment of others and affect nuclear receptor transactivation. Our data suggest that there is a functional difference between the presence of the NER factors at the promoters (which requires XPC) and the NER factors at the distal regions of the gene (which requires CSB). While the latter may be a repair function, the former is a function with respect to transcription unveiled in the current study.
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PMID:NER factors are recruited to active promoters and facilitate chromatin modification for transcription in the absence of exogenous genotoxic attack. 2038 89


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