Transcription factor II H (TF_IIH) is an important protein complex, having roles in transcription of various protein-coding genes and DNA nucleotide excision repair (NER) pathways. TF_IIH 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 TF_IIH in 1992.^[1][2]

TF_IIH consists of ten subunits, 7 of which (ERCC2/XPD, ERCC3/XPB, GTF2H1/p62, GTF2H4/p52, GTF2H2/p44, GTF2H3/p34 and GTF2H5/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 TF_IIH 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, TF_IIH is also involved in nucleotide excision repair.

History of TF_IIH

Before TF_IIH identified it, it had several names. It was isolated in 1989 isolated from rat liver, known by factor transcription delta. When identified from cancer cells it was known that time as Basic transcription factor 2. Also, when isolated from yeast it was termed transcription factor B. Finally, in 1992 known as TF_IIH.^[4]

Structure of TF_IIH

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.^[6]

Functions

General function of TF_IIH:

1. Initiation transcription of protein- coding gene.^[7]
2. DNA nucleotide repairing.^[7]

(NER)TF_IIH 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.^[8][9] Purified TF_IIH has role in stopping further RNA synthesis by activating the cyclic peptide α-amanitin.

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]

Disease

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.^[11] In addition to genetic variations, virus-encoded proteins also target TF_IIH.^[12]

DNA repair

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 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 TF_IIH components, often display features of premature aging^[10][13] (see DNA damage theory of aging).

Inhibitors

Potent, bioactive natural products like triptolide that inhibit mammalian transcription via inhibition of the XPB subunit of the general transcription factor TF_IIH has been recently reported as a glucose conjugate for targeting hypoxic cancer cells with increased glucose transporter expression.^[14]

Mechanism of TF_IIH repairing DNA damaged sequence