Transcription factor II H

Transcription factor II H (TF_IIH) is a multi-subunit protein complex involved in both the transcription of protein-coding genes and the nucleotide excision repair (NER) pathway. TF_IIH was first identified in 1989 as general transcription factor-δ or basic transcription factor 2, an essential factor for transcription in vitro. It was subsequently isolated from yeast and officially named TF_IIH in 1992.^[1][2]

general transcription factor IIH, polypeptide 1, 62kDa
Identifiers
Symbol	GTF2H1
Alt. symbols	BTF2
NCBI gene	2965
HGNC	4655
OMIM	189972
RefSeq	NM_005316
UniProt	P32780
Other data
Locus	Chr. 11 p15.1-p14
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general transcription factor IIH, polypeptide 2, 44kDa
Identifiers
Symbol	GTF2H2
Alt. symbols	BTF2, TFIIH, BTF2P44, T-BTF2P44
NCBI gene	2966
HGNC	4656
OMIM	601748
RefSeq	NM_001515
UniProt	Q13888
Other data
Locus	Chr. 5 q12.2-13.3
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general transcription factor IIH, polypeptide 3, 34kDa
Identifiers
Symbol	GTF2H3
Alt. symbols	BTF2, TFIIH
NCBI gene	2967
HGNC	4657
OMIM	601750
RefSeq	NM_001516
UniProt	Q13889
Other data
Locus	Chr. 12 q24.31
Search for Structures Swiss-model Domains InterPro

TF_IIH is composed of ten subunits. Seven of these—ERCC2/XPD, ERCC3/XPB, GTF2H1/p62, GTF2H4/p52, GTF2H2/p44, GTF2H3/p34, and GTF2H5/TTDA—constitute the core complex. The remaining three subunits—CDK7, MAT1, and cyclin H—form the cyclin-activating kinase (CAK) subcomplex, which is tethered to the core via the XPD protein.^[3] Among the core subunits, ERCC2/XPD and ERCC3/XPB possess helicase and ATPase activities and are essential for unwinding DNA to form the transcription bubble. These activities are necessary during transcription in vitro only when the DNA template is not already denatured or is supercoiled.

The CAK subunits, CDK7 and cyclin H, are responsible for the phosphorylation of serine residues in the C-terminal domain of RNA polymerase II, as well as potentially other targets involved in the cell cycle. In addition to its essential role in transcription initiation, TF_IIH also plays a critical part in nucleotide excision repair.

History

Before being designated as TF_IIH, the complex was known by several names. It was first isolated in 1989 from rat liver and referred to as transcription factor δ. When identified in cancer cells, it was called basic transcription factor 2, and when isolated from yeast, it was known as transcription factor B. The complex was officially named TF_IIH in 1992.^[4]

Structure

TF_IIH is a ten‐subunit complex; seven of these subunits comprise the "core" whereas three comprise the dissociable "CAK" (CDK-activating Kinase) module.^[5] The core consists of subunits XPB, XPD, p62, p52, p44, p34 and p8 while CAK is composed of CDK7, cyclin H, and MAT1.^[5]

Function

General functions of TF_IIH include:

1. Initiating transcription of protein-coding genes^[6]
2. Repairing DNA^[6]

Gene transcription

TF_IIH is a general transcription factor that helps recruit RNA polymerase II (Pol II) to gene promoters. It acts as a DNA translocase, sliding along the DNA while feeding it into the RNA polymerase II cleft, thereby generating torsional strain that facilitates local DNA unwinding.^[7] TF_IIH also plays a critical role in nucleotide excision repair (NER), where it unwinds DNA at sites of damage following lesion recognition by either the global genome repair (GGR) or transcription-coupled repair (TCR) pathway.^[8][9]

DNA repair

Mechanism of TF_IIH repairing DNA damaged sequence

TF_IIH 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 types of damage that distort normal base pairing, including bulky chemical damage and UV-induced damage. Individuals with mutational defects in genes specifying protein components that catalyze the NER pathway, including the TF_IIH components, often display features of premature aging.^[10][11]

Clinical signficance

Trichothiodystrophy

Mutation in genes ERCC3 (XPB), ERCC2 (XPD) or GTF2H5 (TTDA) cause trichothiodystrophy, a condition characterized by photosensitivity, ichthyosis, brittle hair and nails, intellectual impairment, decreased fertility and/or short stature.^[10]

Cancer

Genetic polymorphisms of genes that encode subunits of TF_IIH 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.^[12]

Viral infection

Virus-encoded proteins target TF_IIH.^[13]

Inhibitors

Potent, bioactive natural products such as triptolide, which inhibit mammalian transcription by targeting the XPB subunit of the general transcription factor TF_IIH, have recently been developed as glucose conjugates to selectively target hypoxic cancer cells with elevated glucose transporter expression.^[14]