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

TF_IIH is composed of ten subunits. Seven of these—ERCC2/XPD,ERCC3/XPB,GTF2H1/p62,GTF2H4/p52,GTF2H2/p44,GTF2H3/p34, andGTF2H5/TTDA—constitute the core complex. The remaining three subunits—CDK7, MAT1, andcyclin 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 andERCC3/XPB possesshelicase andATPase activities and are essential for unwinding DNA to form thetranscription bubble. These activities are necessary during transcription in vitro only when the DNA template is not alreadydenatured or issupercoiled.

The CAK subunits,CDK7 andcyclin H, are responsible for thephosphorylation ofserine residues in theC-terminal domain of RNA polymerase II, as well as potentially other targets involved in thecell cycle. In addition to its essential role in transcription initiation, TF_IIH also plays a critical part innucleotide excision repair.

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]

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 andp8 while CAK is composed ofCDK7,cyclin H, andMAT1.^[5]

General functions of TF_IIH include:

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

TF_IIH is a generaltranscription factor that helps recruitRNA polymerase II (Pol II) togene promoters. It acts as a DNAtranslocase, sliding along the DNA while feeding it into the RNA polymerase II cleft, thereby generating torsional strain that facilitates localDNA unwinding.^[7]TF_IIH also plays a critical role innucleotide 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]

TF_IIH participates innucleotide excision repair (NER) by opening theDNA 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 ofpremature aging.^[10][11]

Mutation in genesERCC3 (XPB),ERCC2 (XPD) orGTF2H5 (TTDA) causetrichothiodystrophy, a condition characterized byphotosensitivity,ichthyosis, brittle hair and nails, intellectual impairment, decreased fertility and/or short stature.^[10]

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, includingxeroderma pigmentosum (XP) or XP combined withCockayne syndrome.^[12]

Virus-encoded proteins target TF_IIH.^[13]

Potent, bioactive natural products such astriptolide, 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]

• Transcription+Factor+TFIIH at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

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