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Transcription factor II H (TFIIH) is an important
protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multidomain enzymes, in which multiple active site, catalytic domains are found in a single polypeptide chain. ...
, having roles in transcription of various
protein-coding genes The human genome is a complete set of nucleic acid sequences for humans, encoded as the DNA within each of the 23 distinct chromosomes in the cell nucleus. A small DNA molecule is found within individual mitochondria. These are usually treated s ...
and DNA
nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. Intercalation (biochemistry), intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single ...
(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 TFIIH in 1992. TFIIH 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. Two of the subunits, ERCC2/XPD and ERCC3/ XPB, have
helicase Helicases are a class of enzymes that are vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic double helix, separating the two hybridized ...
and
ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, ATP hydrolase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or ...
activities and help create the
transcription bubble A transcription bubble is a molecular structure formed during the initialization of DNA transcription, when a limited portion of the DNA double helix is unwound, providing enough space for RNA polymerase (RNAP) to bind to the template strand and ...
. In a test tube, these subunits are only required for transcription if the
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
template is not already denatured or if it is supercoiled. Two other TFIIH subunits, CDK7 and cyclin H,
phosphorylate In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s on the RNA polymerase II
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
domain and possibly other proteins involved in the
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
. Next to a vital function in transcription initiation, TFIIH is also involved in
nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. Intercalation (biochemistry), intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single ...
.


History of TFIIH

Before TFIIH 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 TFIIH.


Structure of TFIIH

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


Functions

General function of TFIIH: # Initiation transcription of protein- coding gene. # DNA nucleotide repairing. (NER)TFIIH is a general transcription factor that acts to recruit RNA Pol II to the promoters of genes.  It functions as a DNA translocase, tracking along the DNA, reeling DNA into the Pol II cleft, and creating torsional strain leading to DNA unwinding.  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. Purified TFIIH has role in stopping further RNA synthesis by activating the cyclic peptide α-amanitin.


Trichothiodystrophy

Mutation in genes ( XPB), ( XPD) or ( TTDA) cause
trichothiodystrophy Trichothiodystrophy (TTD) is an autosomal recessive inherited disorder characterised by brittle hair and intellectual impairment. The word breaks down into ''tricho'' – "hair", '' thio'' – "sulphur", and ''dystrophy'' – "wasting away" or lit ...
, a condition characterized by
photosensitivity Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light. In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished, photoallergy and phototoxicit ...
,
ichthyosis Ichthyosis is a family of genetic disorder, genetic skin disorders characterized by Xeroderma, dry, Scleroderma, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, underlying genetic cau ...
, brittle hair and nails, intellectual impairment, decreased fertility and/or short stature.


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 Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in su ...
(XP) or XP combined with
Cockayne syndrome Cockayne syndrome (CS), also called Neill-Dingwall syndrome, is a rare and fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight ( photo ...
. In addition to genetic variations, virus-encoded proteins also target TFIIH.


DNA repair

TFIIH participates in
nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. Intercalation (biochemistry), intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single ...
(NER) by opening the
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
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 (see
DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of DNA damage (naturally occurring), naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although ...
).


Inhibitors

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


Mechanism of TFIIH repairing DNA damaged sequence


References


External links

* Gene expression Transcription factors {{biochem-stub