Alternative titles; symbols
HGNC Approved Gene Symbol: GTF2H1
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38) : 11:18,322,567-18,367,045 (from NCBI)
Phosphorylation of the C-terminal domain of the largest subunit of RNA polymerase II (POLR2A; 180660) is believed to control the transition from transcription initiation to elongation. The general transcription factor TFIIH contains a kinase activity capable of phosphorylating this domain (Lu et al., 1992). Factors that promote the association of RNA polymerase II with the preinitiation complex stimulate this activity. TFIIE, which is required for the stable association of TFIIH with the preinitiation complex, affects the processivity of TFIIH kinase. TFIIH is a multisubunit factor consisting of at least 5 polypeptides of 92 (133510), 62, 43 (601748), 40, and 35 (601750) kD (Flores et al., 1992). A 52-kD subunit (601760) has also been identified as a component of the TFIIH 'core,' along with p89, p62, p44, and p34 (Marinoni et al., 1997). Lu et al. (1992) expressed the belief that TFIIH is the human counterpart of the yeast general transcription factor b. See also 133530 and Habraken et al. (1996).
Shiekhattar et al. (1995) purified TFIIH and found that it contained material that reacted with antibodies to cyclin-dependent kinase 7 (CDK7; 601955) and cyclin H (601953). The authors confirmed the presence of the CDK-activating kinase complex as a distinct component of TFIIH, suggesting a link, by the phosphorylation of the cell division cycle 2 (116940) or CDK2 (116953) genes, between TFIIH and the processes of transcription, DNA repair, and cell cycle progression.
Mammalian CDK8 (603184) and cyclin C (123838) are components of the RNA polymerase II holoenzyme complex, where they function as a protein kinase that phosphorylates the C-terminal domain of the largest subunit of RNA polymerase II. The CDK8/cyclin C protein complex is also found in a number of mammalian 'Mediator'(see 602984)-like protein complexes, which repress activated transcription independently of the C-terminal domain in vitro. Akoulitchev et al. (2000) demonstrated that CDK8/cyclin C can regulate transcription by targeting the CDK7/cyclin H subunits of TFIIH. CDK8 phosphorylates mammalian cyclin H at serine-5 and serine-304 both in vitro and in vivo, in the vicinity of its functionally unique N- and C-terminal alpha-helical domains. This phosphorylation represses both the ability of TFIIH to activate transcription and its C-terminal kinase activity. In addition, mimicking CDK8 phosphorylation of cyclin H in vivo has a dominant-negative effect on cell growth. Akoulitchev et al. (2000) concluded that their results linked the Mediator complex and the basal transcription machinery by a regulatory pathway involving 2 cyclin-dependent kinases. This pathway appears to be unique to higher organisms.
High levels of gene transcription by RNA polymerase II depend on high rates of transcription initiation and reinitiation. Initiation requires recruitment of the complete transcription machinery to a promoter, a process facilitated by activators and chromatin remodeling factors. Reinitiation is thought to occur through a different pathway. After initiation, a subset of the transcription machinery remains at the promoter, forming a platform for assembly of a second transcription complex. Yudkovsky et al. (2000) described the isolation of a reinitiation intermediate in yeast that includes transcription factors TFIID, TFIIA (see 600520), TFIIH, TFIIE, and Mediator. This intermediate can act as a scaffold for formation of a functional reinitiation complex. Formation of this scaffold is dependent on ATP and TFIIH. In yeast, the scaffold is stabilized in the presence of the activator Gal4-VP16, but not Gal4-AH, suggesting a new role for some activators and Mediator in promoting high levels of transcription.
Hoogstraten et al. (2002) generated cell lines expressing functional GFP-tagged TFIIH. TFIIH was homogeneously distributed throughout the nucleus with nucleolar accumulations. The authors provided in vivo evidence for involvement of TFIIH in RNA polymerase I transcription. Photobleaching revealed that TFIIH moved freely and was engaged in RNA polymerase I and II transcription for approximately 25 seconds and approximately 6 seconds, respectively. TFIIH readily switched between transcription and repair sites, where it was immobilized for 4 minutes, without large-scale alterations in composition. These findings supported a model of diffusion and random collision of individual components that permits a quick and versatile response to changing conditions.
Trichothiodystrophy (TTD; 601675) is a rare hereditary multisystem disorder associated with defects in nucleotide excision repair (NER) as a consequence of mutation in XPD (126340), XPB (133510), or TTDA (608780), 3 genes that are related to TFIIH. Botta et al. (2002) showed that all the mutations found in TTD cases, irrespective of whether they were homozygotes, hemizygotes, or compound heterozygotes, caused a substantial and specific reduction (by up to 70%) in the cellular concentration of TFIIH. However, the degree of reduction in TFIIH did not correlate with the severity of the pathologic phenotype, suggesting that the severity of the clinical features in TTD cannot be related solely to the effects of mutations on the stability of TFIIH. Mild reductions (up to 40%) in TFIIH content were also found in some, but not all, cell strains from patients with xeroderma pigmentosum (see 278700). Botta et al. (2002) concluded that the severity of the clinical features in TTD patients and the clinical outcome of differentially mutated XPD proteins may depend both on the effects that each mutation has on the stability of TFIIH as well as on the transcriptional activity of the residual TFIIH complexes.
Initiation of transcription by RNA polymerase II is a complex process requiring, in addition to the polymerase itself, 7 auxiliary factors. Entry of the polymerase into the transcription cycle is mediated by transcription factor TFIIF (see 189968) and requires a DNA-protein complex composed of the TATA-binding protein subunit of TFIID (313650) in association with the TATA motif and TFIIB (189963), the so-called DB complex. The largest subunit of mammalian RNA polymerase II (POLR2A; 180660) contains a heptapeptide repeat, YSPTSPS in the single-letter amino acid code, occurring 52 times at its C terminus. Because the heptapeptide contains serine, threonine, and tyrosine, it is prone to phosphorylation. As a result, RNA polymerase II occurs in 2 forms in vivo: a highly phosphorylated II(O) form and a nonphosphorylated II(A) form. The nonphosphorylated form of RNA polymerase II is recruited by TFIIF to the DB complex. This complex is then recognized by TFIIE (189962), TFIIH, and TFIIJ, which enter the transcription cycle in that order, to generate a transcription-competent complex (summary by Lu et al., 1992).
Giglia-Mari et al. (2004) tabulated the 10 subunits of TFIIH. They referred to GTF2H1 as TFB1.
Heng et al. (1994) mapped the GTF2H1 gene to 11p15.1-p14 by fluorescence in situ hybridization.
By PCR analysis on hybrid DNAs and the YACs, Fantes et al. (1995) placed the GTF2H1 gene in their interval XX between the LDHA/C (150000; 150150) and the SAA (104750) genes. Furthermore, restriction mapping placed GTF2H1 within 50 kb of LDHA.
Fantes et al. (1995) described a detailed physical map of 11p, extending from the distal part of 11p13 through the entirety of 11p14 to proximal 11p15.1. The primary level of mapping was based on chromosome breakpoints that divided the region into 20 intervals. At higher resolution, YACs covered approximately 12 Mb of the region. The map incorporated 18 known genes, including precise localization of the GTF2H1 gene encoding the 62-kD subunit of TFIIH.
Akoulitchev, S., Chuikov, S., Reinberg, D. TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407: 102-106, 2000. [PubMed: 10993082] [Full Text: https://doi.org/10.1038/35024111]
Botta, E., Nardo, T., Lehmann, A. R., Egly, J.-M., Pedrini, A. M., Stefanini, M. Reduced level of the repair/transcription factor TFIIH in trichothiodystrophy. Hum. Molec. Genet. 11: 2919-2928, 2002. [PubMed: 12393803] [Full Text: https://doi.org/10.1093/hmg/11.23.2919]
Fantes, J. A., Oghene, K., Boyle, S., Danes, S., Fletcher, J. M., Bruford, E. A., Williamson, K., Seawright, A., Schedl, A., Hanson, I., Zehetner, G., Bhogal, R., Lehrach, H., Gregory, S., Williams, J., Little, P. F. R., Sellar, G. C., Hoovers, J., Mannens, M., Weissenbach, J., Junien, C., van Heyningen, V., Bickmore, W. A. A high-resolution integrated physical, cytogenetic, and genetic map of human chromosome 11: distal p13 to proximal p15.1. Genomics 25: 447-461, 1995. [PubMed: 7789978] [Full Text: https://doi.org/10.1016/0888-7543(95)80045-n]
Flores, O., Lu, H., Reinberg, D. Factors involved in specific transcription by mammalian RNA polymerase II: identification and characterization of factor IIH. J. Biol. Chem. 267: 2786-2793, 1992. [PubMed: 1733973]
Giglia-Mari, G., Coin, F., Ranish, J. A., Hoogstraten, D., Theil, A., Wijgers, N., Jaspers, N. G. J., Raams, A., Argentini, M., van der Spek, P. J., Botta, E., Stefanini, M., Egly, J.-M., Aebersold, R., Hoeijmakers, J. H. J., Vermeulen, W. A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A. Nature Genet. 36: 714-719, 2004. [PubMed: 15220921] [Full Text: https://doi.org/10.1038/ng1387]
Habraken, Y., Sung, P., Prakash, S., Prakash, L. Transcription factor TFIIH and DNA endonuclease Rad2 constitute yeast nucleotide excision repair factor 3: implications for nucleotide excision repair and Cockayne syndrome. Proc. Nat. Acad. Sci. 93: 10718-10722, 1996. [PubMed: 8855246] [Full Text: https://doi.org/10.1073/pnas.93.20.10718]
Heng, H. H. Q., Xiao, H., Shi, X.-M., Greenblatt, J., Tsui, L.-C. Genes encoding general initiation factors for RNA polymerase II transcription are dispersed in the human genome. Hum. Molec. Genet. 3: 61-64, 1994. [PubMed: 8162052] [Full Text: https://doi.org/10.1093/hmg/3.1.61]
Hoogstraten, D., Nigg, A. L., Heath, H., Mullenders, L. H. F., van Driel, R., Hoeijmakers, J. H. J., Vermeulen, W., Houtsmuller, A. B. Rapid switching of TFIIH between RNA polymerase I and II transcription and DNA repair in vivo. Molec. Cell 10: 1163-1174, 2002. [PubMed: 12453423] [Full Text: https://doi.org/10.1016/s1097-2765(02)00709-8]
Lu, H., Zawel, L., Fisher, L., Egly, J.-M., Reinberg, D. Human general transcription factor IIH phosphorylates the C-terminal domain of RNA polymerase II. Nature 358: 641-645, 1992. [PubMed: 1495560] [Full Text: https://doi.org/10.1038/358641a0]
Marinoni, J.-C., Roy, R., Vermeulen, W., Miniou, P., Lutz, Y., Weeda, G., Seroz, T., Gomez, D. M., Hoeijmakers, J. H. J., Egly, J.-M. Cloning and characterization of p52, the fifth subunit of the core of the transcription/DNA repair factor TFIIH. EMBO J. 16: 1093-1102, 1997. [PubMed: 9118947] [Full Text: https://doi.org/10.1093/emboj/16.5.1093]
Shiekhattar, R., Mermelstein, F., Fisher, R. P., Drapkin, R., Dynlacht, B., Wessling, H. C., Morgan, D. O., Reinberg, D. Cdk-activating kinase complex is a component of human transcription factor TFIIH. Nature 374: 283-287, 1995. [PubMed: 7533895] [Full Text: https://doi.org/10.1038/374283a0]
Yudkovsky, N., Ranish, J. A., Hahn, S. A transcription reinitiation intermediate that is stabilized by activator. Nature 408: 225-229, 2000. [PubMed: 11089979] [Full Text: https://doi.org/10.1038/35041603]