Transcription factor II H


Transcription factor II H is a multi-subunit protein complex involved in both the transcription of protein-coding genes and the nucleotide excision repair pathway. TFIIH 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 TFIIH in 1992.
TFIIH 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 subcomplex, which is tethered to the core via the XPD protein. 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, TFIIH also plays a critical part in nucleotide excision repair.

History

Before being designated as TFIIH, 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 TFIIH in 1992.

Structure

TFIIH is a ten‐subunit complex; seven of these subunits comprise the "core" whereas three comprise the dissociable "CAK" module. The core consists of subunits XPB, XPD, p62, p52, p44, p34 and p8 while CAK is composed of CDK7, cyclin H, and MAT1.

Function

General functions of TFIIH include:
  1. Initiating transcription of protein-coding genes
  2. Repairing DNA

    Gene transcription

TFIIH is a general transcription factor that helps recruit RNA polymerase 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.
TFIIH also plays a critical role in nucleotide excision repair, where it unwinds DNA at sites of damage following lesion recognition by either the global genome repair or transcription-coupled repair pathway.

DNA repair

TFIIH participates in nucleotide excision repair 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 TFIIH components, often display features of DNA damage [theory of aging|premature aging].

Clinical significance

Trichothiodystrophy

Mutation in genes , or cause trichothiodystrophy, a condition characterized by photosensitivity, ichthyosis, brittle hair and nails, intellectual impairment, decreased fertility and/or short stature.

Cancer

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 can lead to a variety of diseases, including xeroderma pigmentosum or XP combined with Cockayne syndrome.

Viral infection

Virus-encoded proteins target TFIIH.

Inhibitors

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