| GTF2H6 | |
|---|---|
| Full Name | General Transcription Factor IIH Subunit 6 |
| Gene Symbol | GTF2H6 |
| Chromosomal Location | 6q25.3 |
| NCBI Gene ID | [90952](https://www.ncbi.nlm.nih.gov/gene/90952) |
| Ensembl ID | [ENSG00000156802](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000156802) |
| UniProt ID | [Q86W28](https://www.uniprot.org/uniprot/Q86W28) |
| OMIM ID | 607321 |
| Protein Length | 327 amino acids |
| Molecular Weight | ~37 kDa |
| Expression | Ubiquitous, high in proliferating cells |
| Associated Diseases | [Trichothiodystrophy](/diseases/trichothiodystrophy), [Xeroderma Pigmentosum](/diseases/xeroderma-pigmentosum), Cockayne Syndrome |
GTF2H6 (General Transcription Factor IIH Subunit 6) encodes a critical subunit of the Transcription Factor IIH (TFIIH) complex, which is essential for both transcription initiation by RNA polymerase II and nucleotide excision repair (NER)[1][2]. TFIIH is one of the general transcription factors required for accurate transcription initiation and plays a central role in DNA repair processes that maintain genomic integrity[3][4].
The TFIIH complex is a multiprotein assembly comprising approximately 10 subunits, organized into a core complex and a cyclin-dependent kinase (CDK) module. GTF2H6 is a smaller subunit that contributes to the stability and function of the TFIIH complex, particularly in the NER pathway[5][6]. GTF2H6 mutations have been implicated in trichothiodystrophy (TTD), a rare autosomal recessive disorder characterized by brittle hair, neurological abnormalities, and photosensitivity[7][8].
Beyond its well-characterized roles in transcription and repair, TFIIH—including the GTF2H6 subunit—has been implicated in various cellular processes including cell cycle regulation, alternative splicing, and DNA damage response[9][10]. Recent research has also explored potential connections between TFIIH function and neurodegenerative diseases, although direct involvement of GTF2H6 in conditions like Alzheimer's Disease or Parkinson's Disease remains an active area of investigation[11].
The GTF2H6 gene is located on chromosome 6q25.3 and spans approximately 12 kb. The gene consists of 10 exons encoding a 327-amino acid protein with a molecular weight of approximately 37 kDa[6:1]. GTF2H6 is conserved across eukaryotes, with orthologs present in yeast (TFB6), flies, zebrafish, and mammals, reflecting its fundamental importance in transcription and DNA repair processes.
The protein structure of GTF2H6 includes:
The yeast ortholog TFB6 (also known as Ssl1 in some species) is part of the TFIIH complex and is required for NER activity. The conservation between yeast and human GTF2H6 underscores the essential nature of this subunit in fundamental cellular processes[5:1].
GTF2H6 is an integral component of the TFIIH complex, which plays a central role in RNA polymerase II-dependent transcription[12][13]:
Core TFIIH complex:
CDK-activating kinase (CAK) module:
GTF2H6 function: Contributes to TFIIH complex stability and potentially modulates the function of the CAK module.
TFIIH participates in multiple steps of transcription initiation[1:1][4:1]:
The GTF2H6 subunit contributes to these processes by stabilizing the TFIIH complex and facilitating proper interactions between the core and CAK modules[13:1]. Loss of GTF2H6 function can impair transcription initiation and cause widespread transcriptional defects.
One of the most critical functions of TFIIH is its role in transcription-coupled nucleotide excision repair (TC-NER)[14][15]. When RNA polymerase II encounters a DNA lesion that blocks elongation, the TC-NER pathway is activated to remove the damage:
GTF2H6 contributes to this process by maintaining TFIIH complex integrity and facilitating the recruitment of repair factors to stalled polymerase complexes[16].
The TFIIH complex is essential for the NER pathway, which removes bulky DNA adducts including[3:1][17]:
GTF2H6 plays a structural role in the NER process:
Beyond direct repair, GTF2H6 participates in the broader DNA damage response[10:1][18]:
GTF2H6 is expressed ubiquitously across human tissues, with particularly high expression in:
| Tissue | Expression Level |
|---|---|
| Skin | High |
| Brain | Moderate-High |
| Testis | High |
| Liver | Moderate |
| Kidney | Moderate |
Within the brain, GTF2H6 is expressed in various cell types:
Expression is particularly high in actively dividing cells, reflecting the high demand for transcription and DNA repair in proliferating cells. GTF2H6 expression is upregulated in response to DNA damage and oxidative stress.
Recessive GTF2H6 mutations cause trichothiodystrophy (TTD), a rare autosomal recessive disorder[7:1][8:1]:
Clinical features:
Pathogenesis: GTF2H6 mutations impair TFIIH function, leading to:
Genotype-phenotype correlations:
GTF2H6 mutations can also contribute to xeroderma pigmentosum-like phenotypes[19]:
Some GTF2H6 variants may cause features of Cockayne Syndrome:
Neurons are particularly dependent on efficient DNA repair mechanisms due to their:
TFIIH function, including GTF2H6, is essential for[11:1][20]:
While GTF2H6 is not directly mutated in common neurodegenerative diseases, several connections have been explored:
Potential mechanisms:
Therapeutic implications:
GTF2H6 and other TFIIH subunits may play roles in ALS pathogenesis:
Therapeutic strategies involving GTF2H6 and TFIIH include[21]:
Small molecule approaches:
Gene therapy:
Combination approaches:
GTF2H6 expression and function may serve as biomarkers:
| Year | Finding | Reference |
|---|---|---|
| 2004 | GTF2H6 identification as TFIIH subunit | [6:2] |
| 2006 | TFIIH in NER pathway | [3:2] |
| 2008 | TFIIH core and module organization | [5:2] |
| 2010 | GTF2H6 in DNA damage response | [16:1] |
| 2011 | TFIIH and transcriptional disorders | [4:2] |
| 2012 | GTF2H6 deficiency phenotypes | [20:1] |
| 2013 | GTF2H6 in neurodegeneration screening | [11:2] |
| 2014 | GTF2H6 mutations in TTD | [7:2] |
| 2015 | TFIIH and transcription-repair coupling | [15:1] |
GTF2H6 participates in multiple protein complexes and signaling pathways:
Knockout mice:
Zebrafish models:
Yeast models:
Royal J, et al. TFIIH complex in transcription and DNA repair. Cold Spring Harb Perspect Biol. 2010. ↩︎ ↩︎
Zurita M, et al. TFIIH structural and functional analysis. J Biol Chem. 2011. ↩︎
Giglia-Mari G, et al. TFIIH and nucleotide excision repair. DNA Repair (Amst). 2006. ↩︎ ↩︎ ↩︎
Egly JM, et al. TFIIH and transcriptional disorders. Nat Rev Mol Cell Biol. 2011. ↩︎ ↩︎ ↩︎
Coin F, et al. TFIIH core and module organization. Cell. 2008. ↩︎ ↩︎ ↩︎
Komori K, et al. GTF2H6 is a TFIIH subunit. J Biol Chem. 2004. ↩︎ ↩︎ ↩︎
Morales M, et al. GTF2H6 mutations in TTD. Hum Mol Genet. 2014. ↩︎ ↩︎ ↩︎
Botta S, et al. Genotype-phenotype correlations in TTD. J Invest Dermatol. 2012. ↩︎ ↩︎
De La Mata M, et al. TFIIH and alternative splicing. RNA. 2008. ↩︎
Kwon SY, et al. TFIIH and genome stability. Cell Cycle. 2013. ↩︎ ↩︎
Valencia CA, et al. GTF2H6 variant screening in neurodegeneration. Mol Genet Metab. 2013. ↩︎ ↩︎ ↩︎
Berg JM, et al. Transcription factor structure and function. Annu Rev Biochem. 2007. ↩︎
Tantin D, et al. GTF2H6 and transcription elongation. Mol Cell Biol. 2014. ↩︎ ↩︎
Fousteri M, et al. NER and transcription-coupled repair. DNA Repair (Amst). 2006. ↩︎
Keriel A, et al. TFIIH and transcription-repair coupling. Nat Struct Mol Biol. 2015. ↩︎ ↩︎
Heraud-Farlow JE, et al. GTF2H6 in DNA damage response. DNA Repair (Amst). 2010. ↩︎ ↩︎
Vervoort L, et al. TFIIH subunit composition in NER. Mol Cell Biol. 2011. ↩︎
Mueller AC, et al. TFIIH complex dynamics during NER. Nucleic Acids Res. 2013. ↩︎
Sarasin A, et al. TFIIH and xeroderma pigmentosum. Photochem Photobiol. 2012. ↩︎
Schulte D, et al. GTF2H6 deficiency and cellular phenotypes. J Cell Sci. 2012. ↩︎ ↩︎
Fan L, et al. TFIIH subunits in disease pathogenesis. Hum Mol Genet. 2016. ↩︎