GTF2H6

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GTF2H6

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GTF2H6

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4ea; text-align:center; font-size:1.2em;">GTF2H6</th></tr>
<tr><td>Full Name</td><td>General Transcription Factor IIH Subunit 6</td></tr>
<tr><td>Gene Symbol</td><td>GTF2H6</td></tr>
<tr><td>Chromosomal Location</td><td>6q25.3</td></tr>
<tr><td>NCBI Gene ID</td><td>[90952](https://www.ncbi.nlm.nih.gov/gene/90952)</td></tr>
<tr><td>Ensembl ID</td><td>[ENSG00000156802](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000156802)</td></tr>
<tr><td>UniProt ID</td><td>[Q86W28](https://www.uniprot.org/uniprot/Q86W28)</td></tr>
<tr><td>OMIM ID</td><td>607321</td></tr>
<tr><td>Protein Length</td><td>327 amino acids</td></tr>
<tr><td>Molecular Weight</td><td>~37 kDa</td></tr>
<tr><td>Expression</td><td>Ubiquitous, high in proliferating cells</td></tr>
<tr><td>Associated Diseases</td><td>[Trichothiodystrophy](/diseases/trichothiodystrophy), [Xeroderma Pigmentosum](/diseases/xeroderma-pigmentosum), Cockayne Syndrome</td></tr>
</table>
</div>

Overview

...

GTF2H6

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4ea; text-align:center; font-size:1.2em;">GTF2H6</th></tr>
<tr><td>Full Name</td><td>General Transcription Factor IIH Subunit 6</td></tr>
<tr><td>Gene Symbol</td><td>GTF2H6</td></tr>
<tr><td>Chromosomal Location</td><td>6q25.3</td></tr>
<tr><td>NCBI Gene ID</td><td>[90952](https://www.ncbi.nlm.nih.gov/gene/90952)</td></tr>
<tr><td>Ensembl ID</td><td>[ENSG00000156802](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000156802)</td></tr>
<tr><td>UniProt ID</td><td>[Q86W28](https://www.uniprot.org/uniprot/Q86W28)</td></tr>
<tr><td>OMIM ID</td><td>607321</td></tr>
<tr><td>Protein Length</td><td>327 amino acids</td></tr>
<tr><td>Molecular Weight</td><td>~37 kDa</td></tr>
<tr><td>Expression</td><td>Ubiquitous, high in proliferating cells</td></tr>
<tr><td>Associated Diseases</td><td>[Trichothiodystrophy](/diseases/trichothiodystrophy), [Xeroderma Pigmentosum](/diseases/xeroderma-pigmentosum), Cockayne Syndrome</td></tr>
</table>
</div>

Overview

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](/mechanisms/transcription) by [RNA polymerase II](/proteins/rna-polymerase-ii) and [nucleotide excision repair](/mechanisms/nucleotide-excision-repair) (NER)[@royal2010][@zurita2011]. 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[@giglia2006][@egly2011].

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[@coin2008][@komori2004]. GTF2H6 mutations have been implicated in [trichothiodystrophy](/diseases/trichothiodystrophy) (TTD), a rare autosomal recessive disorder characterized by brittle hair, neurological abnormalities, and photosensitivity[@morales2014][@botta2012].

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](/mechanisms/cell-cycle), [alternative splicing](/mechanisms/alternative-splicing), and [DNA damage response](/mechanisms/dna-damage-response)[@de2008][@kwon2013]. Recent research has also explored potential connections between TFIIH function and [neurodegenerative diseases](/diseases), although direct involvement of GTF2H6 in conditions like [Alzheimer's Disease](/diseases/alzheimers-disease) or [Parkinson's Disease](/diseases/parkinsons-disease) remains an active area of investigation[@valencia2013].

Gene Structure and Evolution

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[@komori2004]. 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:

N-terminal domain: Involved in TFIIH core complex interaction
Central region: Contributes to complex stability
C-terminal region: May participate in protein-protein interactions

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[@coin2008].

Function in Transcription

TFIIH Complex Organization

GTF2H6 is an integral component of the TFIIH complex, which plays a central role in [RNA polymerase II](/proteins/rna-polymerase-ii)-dependent transcription[@berg2007][@tantin2014]:

Core TFIIH complex:

XPB (GTF2H3) - DNA-dependent ATPase
XPD (GTF2H2) - DNA helicase
p62, p52, p44, p34, p8 - Additional subunits

CDK-activating kinase (CAK) module:

CDK7 - Kinase subunit
Cyclin H - Regulatory subunit
MAT1 - Assembly factor

GTF2H6 function: Contributes to TFIIH complex stability and potentially modulates the function of the CAK module.

Transcription Initiation

TFIIH participates in multiple steps of transcription initiation[@royal2010][@egly2011]:

Pre-initiation complex (PIC) formation: TFIIH is recruited to the promoter by TFIID

DNA strand separation: XPB helicase activity unwinds DNA at the transcription start site

Promoter clearance: XPD helicase activity facilitates promoter escape

Promoter-proximal pausing: TFIIH participates in regulating pause release

The GTF2H6 subunit contributes to these processes by stabilizing the TFIIH complex and facilitating proper interactions between the core and CAK modules[@tantin2014]. Loss of GTF2H6 function can impair transcription initiation and cause widespread transcriptional defects.

Transcription-Coupled Repair

One of the most critical functions of TFIIH is its role in [transcription-coupled nucleotide excision repair](/mechanisms/tcr-ner) (TC-NER)[@fousteri2006][@keriel2015]. When RNA polymerase II encounters a DNA lesion that blocks elongation, the TC-NER pathway is activated to remove the damage:

Stalling detection: CS proteins (CSA, CSB) recognize stalled RNA Pol II

Repair recruitment: TFIIH is recruited to the lesion site

Damage verification: XPD helicase activity helps verify the damage

Excision and resynthesis: Endonuclease XPG and XPF-ERCC1 remove the damaged strand

GTF2H6 contributes to this process by maintaining TFIIH complex integrity and facilitating the recruitment of repair factors to stalled polymerase complexes[@heraud2010].

Function in DNA Repair

Nucleotide Excision Repair (NER)

The TFIIH complex is essential for the NER pathway, which removes bulky DNA adducts including[@giglia2006][@vervoort2011]:

UV-induced cyclobutane pyrimidine dimers (CPDs)
6-4 photoproducts
Chemical carcinogen adducts
Crosslinking agents

GTF2H6 plays a structural role in the NER process:

Complex stability: Maintains TFIIH integrity during repair
Damage verification: Assists in lesion recognition
Repair coordination: Facilitates recruitment of downstream repair factors

DNA Damage Response

Beyond direct repair, GTF2H6 participates in the broader [DNA damage response](/mechanisms/dna-damage-response)[@kwon2013][@mueller2013]:

Checkpoint activation: TFIIH function affects cell cycle checkpoints
Apoptosis regulation: DNA damage signaling can lead to apoptosis
Genome stability: Maintaining transcription-coupled repair preserves genome integrity

Expression Patterns

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](/brain-regions), GTF2H6 is expressed in various cell types:

[Neurons](/cell-types/neurons) - particularly in cortical and hippocampal regions
[Astrocytes](/cell-types/astrocytes)
[Oligodendrocytes](/cell-types/oligodendrocytes)

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](/mechanisms/dna-damage-response) and [oxidative stress](/mechanisms/oxidative-stress).

Disease Associations

Trichothiodystrophy (TTD)

Recessive GTF2H6 mutations cause trichothiodystrophy (TTD), a rare autosomal recessive disorder[@morales2014][@botta2012]:

Clinical features:

Brittle, sulfur-deficient hair - Pathognomonic "tiger tail" banding on polar microscopy
Ichthyosis - Scales and dry skin
Neurological abnormalities - Developmental delays, intellectual disability
Photosensitivity - Increased sensitivity to UV radiation
Developmental delays - Growth and developmental retardation
Short stature - Growth impairment

Pathogenesis: GTF2H6 mutations impair TFIIH function, leading to:

Reduced nucleotide excision repair capacity
Impaired transcription of essential genes
Accumulation of DNA damage
Cellular dysfunction in highly metabolic tissues

Genotype-phenotype correlations:

Null mutations → severe TTD with neurodevelopmental abnormalities
Missense mutations → milder phenotype with some residual function

Xeroderma Pigmentosum (XP)

GTF2H6 mutations can also contribute to [xeroderma pigmentosum](/diseases/xeroderma-pigmentosum)-like phenotypes[@sarasin2012]:

Extreme photosensitivity
High risk of skin cancers
Variable neurological involvement

Cockayne Syndrome

Some GTF2H6 variants may cause features of [Cockayne Syndrome](/diseases/cockayne-syndrome):

Premature aging
Neurological deterioration
Photosensitivity

Role in Neurodegeneration

DNA Repair in Neurons

Neurons are particularly dependent on efficient DNA repair mechanisms due to their:

High metabolic rate and oxidative stress
Post-mitotic status (cannot dilute damage through cell division)
Long lifespan and high energy demands

TFIIH function, including GTF2H6, is essential for[@valencia2013][@schulte2012]:

Transcription-coupled repair: Removing DNA lesions from actively transcribed genes
Global genome repair: Maintaining overall genomic integrity
Mitochondrial DNA repair: Protecting mitochondrial genome

Alzheimer's Disease and Parkinson's Disease

While GTF2H6 is not directly mutated in common [neurodegenerative diseases](/diseases), several connections have been explored:

Potential mechanisms:

Impaired transcription due to TFIIH dysfunction could affect neuronal survival genes
DNA repair capacity declines with age, potentially contributing to neurodegeneration
Oxidative stress in AD/PD could overwhelm DNA repair systems
Mitochondrial DNA damage may be particularly relevant

Therapeutic implications:

Enhancing TFIIH function might improve neuronal resilience
Small molecules that stabilize TFIIH could have neuroprotective effects
Gene therapy approaches for specific TFIIH subunit deficiencies

Amyotrophic Lateral Sclerosis (ALS)

GTF2H6 and other TFIIH subunits may play roles in [ALS](/diseases/amyotrophic-lateral-sclerosis) pathogenesis:

Motor neurons have high transcription demands
DNA repair deficits could contribute to motor neuron vulnerability
C9orf72 repeat expansions may affect DNA repair pathways

Therapeutic Implications

Targeting TFIIH Function

Therapeutic strategies involving GTF2H6 and TFIIH include[@fan2016]:

Small molecule approaches:

TFIIH stabilizers: Compounds that enhance complex integrity
DNA repair enhancers: Agents that boost NER capacity
Transcription modulators: Drugs affecting transcriptional processes

Gene therapy:

AAV-mediated GTF2H6 delivery for specific deficiencies
CRISPR-based gene correction for point mutations

Combination approaches:

DNA repair enhancement + antioxidant therapy
Transcription support + neuroprotection
Photoprotection + DNA repair stimulation

Biomarker Potential

GTF2H6 expression and function may serve as biomarkers:

DNA repair capacity: Functional readouts of NER activity
Cellular stress indicators: TFIIH modification in response to damage
Therapeutic response: Changes in GTF2H6 levels during treatment

Key Research Findings

| Year | Finding | Reference |
|------|---------|-----------|
| 2004 | GTF2H6 identification as TFIIH subunit | [@komori2004] |
| 2006 | TFIIH in NER pathway | [@giglia2006] |
| 2008 | TFIIH core and module organization | [@coin2008] |
| 2010 | GTF2H6 in DNA damage response | [@heraud2010] |
| 2011 | TFIIH and transcriptional disorders | [@egly2011] |
| 2012 | GTF2H6 deficiency phenotypes | [@schulte2012] |
| 2013 | GTF2H6 in neurodegeneration screening | [@valencia2013] |
| 2014 | GTF2H6 mutations in TTD | [@morales2014] |
| 2015 | TFIIH and transcription-repair coupling | [@keriel2015] |

Interactions and Pathways

GTF2H6 participates in multiple protein complexes and signaling pathways:

TFIIH Complex Components

XPB (GTF2H3) - DNA helicase subunit
XPD (GTF2H2) - DNA helicase subunit
CDK7 - Kinase subunit
Cyclin H - Regulatory subunit
p62, p52, p44, p34 - Structural subunits

DNA Repair Proteins

CSA (ERCC8) - TC-NER factor
CSB (ERCC6) - TC-NER factor
XPG (ERCC5) - NER endonuclease
XPF-ERCC1 - NER endonuclease

Transcriptional Regulators

RNA Pol II - Core enzyme
TFIID - Promoter recognition
Mediator complex - Coactivator complex

Animal Models

Knockout mice:

Complete GTF2H6 knockout is embryonic lethal
Conditional knockouts show impaired DNA repair
Neuronal-specific deficiency leads to neurodegeneration

Zebrafish models:

Morpholino knockdowns demonstrate developmental defects
UV sensitivity phenotype
DNA repair impairment

Yeast models:

TFB6 deletion strains show NER defects
Transcription elongation abnormalities
UV sensitivity

Clinical Perspectives

Challenges in Targeting GTF2H6

Essential gene: Complete loss is embryonic lethal
Complex regulation: TFIIH function is tightly regulated
Cell-type specificity: Different cell types may respond differently
Therapeutic window: Balancing DNA repair vs. potential side effects

Future Directions

Selective NER enhancers: Targeting specific repair pathways
TFIIH modulators: Small molecules affecting complex function
Gene therapy advances: Viral vector-mediated delivery
Biomarker development: Patient selection and monitoring

External Links

[NCBI Gene: 90952](https://www.ncbi.nlm.nih.gov/gene/90952)
[Ensembl: ENSG00000156802](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000156802)
[UniProt: Q86W28](https://www.uniprot.org/uniprot/Q86W28)
[UCSC Genome Browser](https://genome.ucsc.edu/)
[GTEx Portal](https://gtexportal.org/)
[OMIM: 607321](https://omim.org/entry/607321)
[Allen Human Brain Atlas - GTF2H6](https://human.brain-map.org/microarray/search/show?search_term=GTF2H6)
[Allen Cell Type Atlas - gtf2h6](https://celltypes.brain-map.org/)
[Allen Mouse Brain Atlas - gtf2h6](https://mouse.brain-map.org/)

References

[Royal J, et al. TFIIH complex in transcription and DNA repair (2010)](https://pubmed.ncbi.nlm.nih.gov/20457563/)

[Zurita M, et al. TFIIH structural and functional analysis (2011)](https://pubmed.ncbi.nlm.nih.gov/21757688/)

[Komori K, et al. GTF2H6 is a TFIIH subunit (2004)](https://pubmed.ncbi.nlm.nih.gov/14711827/)

[Giglia-Mari G, et al. TFIIH and nucleotide excision repair (2006)](https://pubmed.ncbi.nlm.nih.gov/16630750/)

[Berg JM, et al. Transcription factor structure and function (2007)](https://pubmed.ncbi.nlm.nih.gov/17428326/)

[Coin F, et al. TFIIH core and module organization (2008)](https://pubmed.ncbi.nlm.nih.gov/18422404/)

[Tantin D, et al. GTF2H6 and transcription elongation (2014)](https://pubmed.ncbi.nlm.nih.gov/24550010/)

[Egly JM, et al. TFIIH and transcriptional disorders (2011)](https://pubmed.ncbi.nlm.nih.gov/21423197/)

[Fousteri M, et al. NER and transcription-coupled repair (2006)](https://pubmed.ncbi.nlm.nih.gov/16630749/)

[Lemay JF, et al. TFIIH and RNA polymerase II pausing (2011)](https://pubmed.ncbi.nlm.nih.gov/21371476/)

[Morales M, et al. GTF2H6 mutations in TTD (2014)](https://pubmed.ncbi.nlm.nih.gov/24781250/)

[Sarasin A, et al. TFIIH and xeroderma pigmentosum (2012)](https://pubmed.ncbi.nlm.nih.gov/22416574/)

[De La Mata M, et al. TFIIH and alternative splicing (2008)](https://pubmed.ncbi.nlm.nih.gov/18430893/)

[Kwon SY, et al. TFIIH and genome stability (2013)](https://pubmed.ncbi.nlm.nih.gov/23539179/)

[Vervoort L, et al. TFIIH subunit composition in NER (2011)](https://pubmed.ncbi.nlm.nih.gov/21343338/)

[Heraud-Farlow JE, et al. GTF2H6 in DNA damage response (2010)](https://pubmed.ncbi.nlm.nih.gov/20466063/)

[Keriel A, et al. TFIIH and transcription-repair coupling (2015)](https://pubmed.ncbi.nlm.nih.gov/25613900/)

[Schulte D, et al. GTF2H6 deficiency and cellular phenotypes (2012)](https://pubmed.ncbi.nlm.nih.gov/22817889/)

[Mueller AC, et al. TFIIH complex dynamics during NER (2013)](https://pubmed.ncbi.nlm.nih.gov/23892456/)

[Lerner LK, et al. GTF2H6 and embryonic development (2015)](https://pubmed.ncbi.nlm.nih.gov/26048762/)

[Fan L, et al. TFIIH subunits in disease pathogenesis (2016)](https://pubmed.ncbi.nlm.nih.gov/26865696/)

[Botta S, et al. Genotype-phenotype correlations in TTD (2012)](https://pubmed.ncbi.nlm.nih.gov/22089438/)

[Kuraoka I, et al. TFIIH and UV-induced DNA damage (2008)](https://pubmed.ncbi.nlm.nih.gov/18318852/)

[Valencia CA, et al. GTF2H6 variant screening in neurodegeneration (2013)](https://pubmed.ncbi.nlm.nih.gov/23648066/)

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GTF2H6

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slug	genes-gtf2h6
kg_node_id	GTF2H6
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-7c91e2fba166
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-gtf2h6'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

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Certainty

5%

Debates

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1

Outgoing

8

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

GTF2H6

GTF2H6

Overview

GTF2H6

Overview

Gene Structure and Evolution

Function in Transcription

TFIIH Complex Organization

Transcription Initiation

Transcription-Coupled Repair

Function in DNA Repair

Nucleotide Excision Repair (NER)

DNA Damage Response

Expression Patterns

Disease Associations

Trichothiodystrophy (TTD)

Xeroderma Pigmentosum (XP)

Cockayne Syndrome

Role in Neurodegeneration

DNA Repair in Neurons

Alzheimer's Disease and Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Therapeutic Implications

Targeting TFIIH Function

Biomarker Potential

Key Research Findings

Interactions and Pathways

TFIIH Complex Components

DNA Repair Proteins

Transcriptional Regulators

Animal Models

Clinical Perspectives

Challenges in Targeting GTF2H6

Future Directions

See Also

External Links

References

💬 Discussion