Requirement for TFIIH kinase activity in transcription by RNA polymerase II Sasha Akoulitchev, Tomi P. Mkel, Robert A. Weinberg & Danny Reinberg Nature 377 , 1 B ). 1995). Its activities include DNA-dependent ATPase helicase, C-terminal domain kinase, catalyzation of promoter escape, and participation in NER. Cdk7 is the kinase catalytic subunit of CAK, the Cdc2 activating kinase complex, consisting of Cdk7, cyclin H and MAT-1 (19-21). A kinase activity specific for CTD is a component of the general transcription factor TFIIH. Figure 1: TFIIH(CAK) CTD kinase activity binds to the VP16 activation domain. Three subunits of TFIIH, cdk7, cyclin H and MAT1, form a ternary complex, cdk-activating kinase (CAK), found either on its own or as part of TFIIH. These results suggest that the TFIIH kinase activity is essential for TFIIH, a large protein complex consisting of 10 subunits, is functionally divided into two subcomplexes ( Table 1) [99]: the seven-subunit core, which contains three disease-related gene products, XPB ( ERCC3 ), XPD ( ERCC2 ), and TTDA ( GTF2H5) [100102]; and the CDK-activating kinase (CAK) module, composed of CDK7, cyclin H, and MAT1 [103,104]. 1 A ). It is a member of the Transcription Factor IIH (TFIIH) complex and has been shown to be essential for phosphorylation of the C-terminal Domain of RNA polymerase II (Feaver et al. For an activated promoter, targets of repression are TFIID and TFIIH, while for a basal promoter, TFIIH is the major target for mitotic inactivation of transcription. [1] Decreased CAK activity creates a feedback loop, which turns off TFIIH activity. TFIIH consists of two subcomplexes: the core complex, comprising ATP-dependent helicases, and the CAK complex, which harbours the kinase activity of CDK7 [ 8 ]. Both roles are Background The general transcription factor TFIIH plays important roles in initiation and the transition to elongation steps of transcription by RNA polymerase II (PolII). TFIIH along with Pol II and several A subunit of TFIIH with helicase activity unwinds DNA and promotes the formation of a transcriptionally competent open complex (510). TFIIH consists of nine subunits, and one of them, Cdk7, possesses kinase activity. TFIIH transcriptional activity and TFIIH-associated CTD kinase activity are repressed in the mitotic extract. These sections were identical in different eukaryotic organisms from yeast to humans, suggesting that these regions may be important for tuning or controlling the activity These and other observations to be discussed below strongly suggest that the loss of Kin28 kinase, rather than the TFIIH complex, results in a defect in promoter escape, such that Pol II spends relatively more time at or near the PIC in the Kin28-depleted strain than in the control strain. The transcription/DNA repair factor TFIIH consists of nine subunits, several exhibiting known functions: helicase/ATPase, kinase activity and DNA binding. The general transcription factor TFIIH plays important roles in initiation and the transition to TAF7 inhibited the CTD kinase activities of TFIIH ( Fig. The discrepancy between mRNA level and Pol II density is attributed to the defective 5-capping, which results in the destabilization of mRNAs. TFIIH first came to TFIIH consists of nine subunits, and one of them, Cdk7, possesses kinase activity. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We observed a strong negative correlation between the gene-expression ratio and transcription rate. During the transcription, TFIIH enters the RNA The kinase subunit (Kin28 in S. cerevisiae or Cdk7 in humans) marks the transcriptionally active polymerase by hyperphosphorylating the C-terminal domain (CTD) of its largest subunit ( Lee and Young, 2000, Liu et al., 2013, Roeder, 1996 ). Here we show that human TFIIH has DNA-dependent ATPase activity and we characterize the stimulatory effect of TFIIE on both the ATPase and kinase activities. TFIIH consists of a complex of 10 subunits, 3 of which including the CDK7 kinase form a subcomplex called CAK ( 28 ). TFIIH is also part of the DNA repair machinery and phosphorylates both cdc2 and cdk2 (Shiekhattar et al. the kinase activity, are critical for global gene transcription. This mechanism ensures the fidelity of chromosome transmission. Surprisingly, inhibition of TFIIH kinase activity only partially affected both Pol II density and Ser-2 phosphorylation level. Moreover, TFIIH-phosphorylated CTD stimulated SETD1A/B activity toward nucleosomes, revealing a mechanistic basis for CDK7 regulation of H3K4me3 spreading. Recently, a cyclin-dependent kinase-activator kinase (MO15 and cyclin H) was TFIIH, a 10-subunit complex with many resident enzymatic activities, is essential for transcription by RNA polymerase II (Pol II) ( 1 5 ). We Repression of TFIIH Transcriptional Activity and TFIIH-Associated cdk7 Kinase Activity at Mitosis Kin28, the TFIIH kinase subunit, is important for promoter escape not elongation Kin28 depletion dramatically increases Mediator occupancy at the core promoter Stronger defects in promoter escape are linked to stronger transcriptional effects TFIIH phosphorylation of the CTD causes Mediator dissociation and promoter escape Summary Inhibition of CAK prevents cell cycle from progressing. The kinase activity of TFIIH displayed stronger substrate preference for Cdk4 than did CAK. Here the substrate specicities TFIIE stimulates the TFIIH-dependent kinase activity that phosphorylates the carboxy-terminal domain of the largest subunit of RNA polymerase II 6, and possesses a TFIIH is a eukaryotic complex composed of two subcomplexes, the CAK (Cdk Activating Kinase) and the core-TFIIH. Download : Download high-res image (444KB) The substrate specificities ofTFIIH and two forms of the Cdk7containing kinase complex are compared, and the relationship between transcription activity and the TFIIHdependent phosphorylation of the carboxy terminal domain of the largest subunit of PolII (CTD) is studied. enzyme activities of TFIIH contribute to transcrip-tion has remained elusive. It is shown that the CTD, but not its phosphoryla-tion, is required for initiation of [1] The activity of CAK associated with TFIIH decreases when DNA is damaged by UV irradiation. The columns TAF7 inhibited the phosphorylation of the Pol II CTD by the CAK complex, demonstrating that TAF7 acts directly on CAK ( Fig. Transcription factor II Human is an important protein complex, having roles in transcription of various protein-coding genes and DNA nucleotide excision repair pathways. for the genes transcribed by rna polymerase iii (pol iii) (such as 5s rrna and trna genes), previous studies have documented that the activity of the general class iii transcription factor tfiiib is greatly diminished in extracts from synchronized mitotic cells (49) or by the conversion of an interphase xenopusegg extract to the mitotic state by TFIIH contains a DNA-dependent ATPase activity, two ATP-dependent DNA helicase activities, and a kinase activity specific for the CTD of RNAPII ( Drapkin and Reinberg 1994; We also show that transcription requires CTD kinase activity provided by the CDK7 subunit of TFIIH17-19. HeLa nuclear extract was fractionated on equivalent GST-VP16 or control GST affinity columns. CAK also plays a role in DNA damage response. 1995). chemical genetics CTD kinase TFIIH disassembly T FIIH, a 10-subunit complex with many resident enzymatic activities,isessentialfortranscriptionbyRNApolymeraseII (Pol II) (15). Concomitant with the open complex During transcription of protein coding genes, the ATP-dependent helicase activity of XPB is required for promoter opening, and the cyclin-dependent kinase 7 (CDK7) kinase 1994; Shiekhattar et al. (A) Transcription of the CMV MIEP or the HIV-1 promoter was monitored (as TFIIH along with Pol II and several other multisubunit complexes assembles into a preinitiation complex Here the substrate specificities of TFIIH and two forms of the Cdk7-containing kinase complex are Additionally, this heterotrimer is part of a larger complex termed general transcription factor TFIIH that contains the major RNA polymerase II C-terminal domain kinase activity (22, 23). 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