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)

Mutations in some subunits of the basal DNA repair and transcription factor II H (TFIIH) are involved in several human genetic disorders. Transcription factor II H interacts with a variety of factors during transcription, including nuclear receptors, tissue-specific transcription factors, chromatin remodeling complexes and RNA, suggesting that, in addition to its essential role in transcription initiation, it also participates as a regulatory factor. Interpretation of the phenotypes produced by mutations in TFIIH is complicated by the recent finding that TFIIH plays a role in RNA polymerase I (RNA Pol I)-mediated transcription. In vitro reconstituted systems and genetic analysis suggest two possible explanations for the transcriptional phenotypes of TFIIH mutations that are not mutually excluding. The first is that different sets of genes require different levels of transcription to maintain a wild-type phenotype. The second suggests that mutations in TFIIH produce specific phenotypes arising from differential interactions of this complex with different transcription regulatory factors.
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PMID:The transcriptional complexity of the TFIIH complex. 1455 Jun 32

Transcription factor II H (TFIIH) is comprised of core TFIIH and Cdk-activating kinase (CAK) complexes. Here, we investigated the molecular and cellular manifestation of the TFIIH compositional changes by XPG truncation mutations. We showed that both core TFIIH and CAK are rapidly recruited to damage sites in repair-proficient cells. Chromatin immunoprecipitation against TFIIH and CAK components revealed a physical engagement of CAK in nucleotide excision repair (NER). While XPD recruitment to DNA damage was normal, CAK was not recruited in severe XP-G and XP-G/CS cells, indicating that the associations of CAK and XPD to core TFIIH are differentially affected. A CAK inhibition approach showed that CAK activity is not required for assembling pre-incision machinery in vivo or for removing genomic photolesions. Instead, CAK is involved in Ser5-phosphorylation and UV-induced degradation of RNA polymerase II. The CAK inhibition impaired transcription from undamaged and UV-damaged reporter, and partially decreased transcription of p53-dependent genes. The overall results demonstrated that a) XP-G/CS mutations affect the disassembly state of TFIIH resulting in the dissociation of CAK, but not XPD from core TFIIH, and b) CAK activity is not essential for global genomic repair but involved in general transcription and damage-induced RNA polymerase II degradation.
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PMID:Dissociation of CAK from core TFIIH reveals a functional link between XP-G/CS and the TFIIH disassembly state. 2054 86

Transcription factor II H (TFIIH) is composed of core TFIIH and Cdk-activating kinase (CAK) complexes. Besides transcription, TFIIH also participates in nucleotide excision repair (NER), verifying DNA lesions through its helicase components XPB and XPD. The assembly state of TFIIH is known to be affected by truncation mutations in xeroderma pigmentosum group G/Cockayne syndrome (XP-G/CS). Here, we showed that CAK component MAT1 was rapidly recruited to UV-induced DNA damage sites, co-localizing with core TFIIH component p62, and dispersed from the damage sites upon completion of DNA repair. While the core TFIIH-CAK association remained intact, MAT1 failed to accumulate at DNA damage sites in fibroblasts harboring XP-B or XP-B/CS mutations. Nevertheless, MAT1, XPD and XPC as well as XPG were able to accumulate at damage sites in XP-D fibroblasts, in which the core TFIIH-CAK association also remained intact. Interestingly, XPG recruitment was impaired in XP-B/CS fibroblasts derived from patients with mild phenotype, but persisted in XP-B/CS fibroblasts from severely affected patients resulting in a nonfunctional preincision complex. An examination of steady-state levels of RNA polymerase II (RNAPII) indicated that UV-induced RNAPII phosphorylation was dramatically reduced in XP-B/CS fibroblasts. These results demonstrated that the CAK rapidly disassociates from the core TFIIH upon assembly of nonfunctional preincision complex in XP-B and XP-B/CS cells. The persistency of nonfunctional preincision complex correlates with the severity exhibited by XP-B patients. The results suggest that XPB and XPD helicases differentially regulate the anchoring of CAK to core TFIIH during damage verification step of NER.
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PMID:Lack of CAK complex accumulation at DNA damage sites in XP-B and XP-B/CS fibroblasts reveals differential regulation of CAK anchoring to core TFIIH by XPB and XPD helicases during nucleotide excision repair. 2308 90

In Drosophila, zygotic genome activation occurs in pre-blastoderm embryos during rapid mitotic divisions. How the transcription machinery is coordinated to achieve this goal in a very brief time span is still poorly understood. Transcription factor II H (TFIIH) is fundamental for transcription initiation by RNA polymerase II (RNAPII). Herein, we show the in vivo dynamics of TFIIH at the onset of transcription in Drosophila embryos. TFIIH shows an oscillatory behaviour between the nucleus and cytoplasm. TFIIH foci are observed from interphase to metaphase, and colocalize with those for RNAPII phosphorylated at serine 5 (RNAPIIS5P) at prophase, suggesting that transcription occurs during the first mitotic phases. Furthermore, embryos with defects in subunits of either the CAK or the core subcomplexes of TFIIH show catastrophic mitosis. Although, transcriptome analyses show altered expression of several maternal genes that participate in mitosis, the global level of RNAPIIS5P in TFIIH mutant embryos is similar to that in the wild type, therefore, a direct role for TFIIH in mitosis cannot be ruled out. These results provide important insights regarding the role of a basal transcription machinery component when the zygotic genome is activated.
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PMID:TFIIH localization is highly dynamic during zygotic genome activation in Drosophila, and its depletion causes catastrophic mitosis. 2964 18