Transcription factor II H

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general transcription factor IIH, polypeptide 1, 62kDa
Identifiers
SymbolGTF2H1
Alt. symbolsBTF2
Entrez2965
HUGO4655
OMIM189972
RefSeqNM_005316
UniProtP32780
Other data
LocusChr. 11 p15.1-p14
general transcription factor IIH, polypeptide 2, 44kDa
Identifiers
SymbolGTF2H2
Alt. symbolsBTF2, TFIIH, BTF2P44, T-BTF2P44
Entrez2966
HUGO4656
OMIM601748
RefSeqNM_001515
UniProtQ13888
Other data
LocusChr. 5 q12.2-13.3
general transcription factor IIH, polypeptide 3, 34kDa
Identifiers
SymbolGTF2H3
Alt. symbolsBTF2, TFIIH
Entrez2967
HUGO4657
OMIM601750
RefSeqNM_001516
UniProtQ13889
Other data
LocusChr. 12 q24.31

Transcription factor II Human (Transcription Factor II H; TFIIH) is an important protein complex, having roles in transcription of various protein-coding genes and DNA nucleotide excision repair (NER) pathways. TFIIH first came to light in 1989 when general transcription factor-δ or basic transcription factor 2 was characterized as an indispensable transcription factor in vitro. This factor was also isolated from yeast and finally named as TFIIH in 1992.[1][2]

TFIIH consists of ten subunits, 7 of which (XPD, XPB, p62, p52, p44, p34 and TTDA) form the core complex. The cyclin activating kinase-subcomplex (CDK7, MAT1, and cyclin H) is linked to the core via the XPD protein[3] Two of the subunits, ERCC2/XPD and ERCC3/XPB, have helicase and ATPase activities and help create the transcription bubble. In a test tube these subunits are only required for transcription if the DNA template is not already denatured or if it is supercoiled.

Two other TFIIH subunits, CDK7 and cyclin H, phosphorylate serine amino acids on the RNA polymerase II C-terminal domain and possibly other proteins involved in the cell cycle. Next to a vital function in transcription initiation, TFIIH is also involved in nucleotide excision repair.

It is responsible for giving the 'go' signal which is why it is assembled last.[citation needed]

Functions

TFIIH is a general transcription factor that acts to recruit RNA Pol II to the promoters of genes.  It functions as a helicase that unwinds DNA.  It also unwinds DNA after a DNA lesion has been recognized by either the global genome repair (GGR) pathway or the transcription-coupled repair (TCR) pathway of NER.[4]

Trichothiodystrophy

Mutation in genes ERCC3/XPB, ERCC2/XPD or TTDA cause trichothiodystrophy, a condition characterized by photosensitivity, ichthyosis, brittle hair and nails, intellectual impairment, decreased fertility and/or short stature.[5]

Disease

Genetic polymorphisms of genes that encode subunits of TFIIH are known to be associated with increased cancer susceptibility in many tissues, e.g.; skin tissue, breast tissue and lung tissue. Mutations in the subunits (such as XPD and XPB) can lead to a variety of diseases, including xeroderma pigmentosum (XP) or XP combined with Cockayne syndrome.[6] In addition to genetic variations, virus-encoded proteins also target TFIIH.[7]

DNA repair

TFIIH participates in nucleotide excision repair (NER) by opening the DNA double helix after damage is initially recognized. NER is a multi-step pathway that removes a wide range of different damages that distort normal base pairing, including bulky chemical damages and UV-induced damages. Individuals with mutational defects in genes specifying protein components that catalyze the NER pathway, including the TFIIH components, often display features of premature aging[5][8] (see DNA damage theory of aging).

References

  1. ↑ Reinberg, D, Flores (1992). "Factors involved in specific transcription by mammalian RNA polymerase II. Identification and characterization of factor IIH". J. Biol. Chem. 267, 2786–2793.
  2. ↑ Kim TK, Ebright RH, Reinberg D (2000). "Mechanism of ATP-dependent promoter melting by transcription factor IIH". Science. 288 (5470): 1418–22. doi:10.1126/science.288.5470.1418. PMID 10827951.
  3. ↑ Lee TI, Young RA (2000). "Transcription of eukaryotic protein-coding genes". Annu. Rev. Genet. 34: 77–137. doi:10.1146/annurev.genet.34.1.77. PMID 11092823.
  4. ↑ Hoogstraten, D., Hoogstraten, D.; et al. (2002). "Rapid switching of TFIIH between RNA polymerase I and II transcription and DNA repair in vivo". Mol. Cell 10, 1163–1174.
  5. ↑ 5.0 5.1 Theil AF, Hoeijmakers JH, Vermeulen W (2014). "TTDA: big impact of a small protein". Exp. Cell Res. 329 (1): 61–8. doi:10.1016/j.yexcr.2014.07.008. PMID 25016283.
  6. ↑ Oh, Kyu-Seon; Khan, Sikandar G.; Jaspers, N.g.j.; Raams, Anja; Ueda, Takahiro; Lehmann, Alan; Friedmann, Peter S.; Emmert, Steffen; Gratchev, Alexi (2006-11-01). "Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome". Human Mutation. 27 (11): 1092–1103. doi:10.1002/humu.20392. ISSN 1098-1004.
  7. ↑ N., Le May; et al. (2004). "TFIIH transcription factor, a target for the Rift Valley hemorrhagic fever virus". Cell 116, 541–550.
  8. ↑ Edifizi D, Schumacher B (2015). "Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms". Biomolecules. 5 (3): 1855–69. doi:10.3390/biom5031855. PMC 4598778. PMID 26287260.

External links


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