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ERCC3
ERCC excision repair 3, TFIIH core complex helicase subunit
The ERCC3 gene provides instructions for the XPB protein, a key component of the TFIIH complex involved in DNA repair and the regulation of gene activity. ERCC3 encodes the XPB protein, which is an essential subunit of the general transcription factor IIH (TFIIH) complex.
ERCC3 is located on the long (q) arm of chromosome 2, at band 2q14.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The ERCC3 gene, also known as XPB, is crucial for producing a protein called XPB. This protein functions as a vital part of the general transcription factor IIH (TFIIH) complex. The TFIIH complex has two primary roles: facilitating gene transcription, which is the initial step in protein synthesis, and repairing damaged DNA within cells.
What the gene does
The XPB protein, encoded by ERCC3, is integral to the TFIIH complex, which performs essential cellular functions. In gene transcription, TFIIH helps regulate gene activity, with XPB and XPD proteins working together to initiate the process. Beyond transcription, TFIIH is critical for DNA repair. Specifically, it participates in nucleotide excision repair (NER), a mechanism cells use to fix DNA damage caused by factors like UV radiation and toxic chemicals. The XPB protein is thought to act as a wedge, unwinding and holding open the DNA strands around the damage site, allowing other proteins to remove the faulty section and replace it with correct DNA.
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Chromosome location
The ERCC3 gene is located on chromosome 2, specifically at position 2q14.3. This gene spans a particular region of the long arm ('q') of chromosome 2.
Protein structure
The ERCC3 protein, consisting of 782 amino acids, features several distinct regions and motifs. An N-terminal Disordered region spans amino acids 1-51, followed by a Nuclear localization signal motif from amino acids 6-18. Another Disordered region is present between amino acids 218-241. Key functional domains include the Helicase ATP-binding domain from amino acids 327-488, which is essential for its enzymatic activity, and the DEVH box motif at amino acids 441-444, critical for helicase function. A C-terminal Helicase C-terminal domain is located from amino acids 542-702.
Key variants
Genetic changes, known as variants, in the ERCC3 gene can affect the normal function of the XPB protein. These variants may alter the protein's ability to participate effectively in DNA repair or gene transcription. The specific impact of a variant often depends on its location and the nature of the change to the protein sequence.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1115_1120dup | p.Trp374Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ERCC3-related disorder |
c.1162C>T | p.Gln388Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Trichothiodystrophy 2, photosensitive |
c.1300G>T | p.Glu434Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Xeroderma pigmentosum group B |
c.1354C>T | p.Arg452Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Xeroderma pigmentosum group B |
c.1588C>T | p.Arg530Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Trichothiodystrophy 2, photosensitive |
c.1720C>T | p.Arg574Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Trichothiodystrophy 2, photosensitive |
c.1735del | p.Tyr579fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1757del | p.Gln586fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.2131C>T | p.Gln711Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.576_583del | p.Val193fs | Pathogenic/Likely pathogenic | ★★☆☆ | ERCC3-related disorder |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the ERCC3 gene are associated with conditions that primarily affect DNA repair mechanisms. These include trichothiodystrophy, a multi-system disorder characterised by brittle hair and, in some cases, extreme sensitivity to UV light. ERCC3 variants are also linked to xeroderma pigmentosum, which causes severe sun sensitivity and increased skin cancer risk, primarily affecting sun-exposed skin and eyes. Some individuals may present with features of both conditions, known as xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ERCC3 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the ERCC3 gene is included in several NHS England Genomic Medicine Service national test directory panels. These include panels for Adult solid tumours cancer susceptibility, Childhood solid tumours, Childhood solid tumours cancer susceptibility, Bilateral congenital or childhood onset cataracts (R31), Foetal anomalies (R21), Intellectual disability, and Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome (R227). It is also listed on the DDG2P panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the ERCC3 gene?
The ERCC3 gene provides instructions for making the XPB protein, which is a crucial part of the TFIIH complex. This complex is vital for both initiating gene transcription and repairing damaged DNA through the nucleotide excision repair pathway.
What conditions are associated with ERCC3 gene variants?
Variants in the ERCC3 gene can be associated with conditions such as trichothiodystrophy, xeroderma pigmentosum, and a combination of both known as xeroderma pigmentosum/Cockayne syndrome complex. These conditions often involve impaired DNA repair and increased sensitivity to UV light.
How does the XPB protein help repair DNA?
The XPB protein, as part of the TFIIH complex, plays a role in unwinding the double-stranded DNA around a site of damage. This action helps to open up the DNA helix, allowing other repair proteins to access and remove the damaged section, which is then replaced with correct DNA.
References
- Oksenych V, Coin F. The long unwinding road: XPB and XPD helicases in damaged DNA opening. Cell cycle (Georgetown, Tex.). 2010. PMID: 20016270
- Lambert WC, Gagna CE, Lambert MW. Xeroderma pigmentosum: its overlap with trichothiodystrophy, Cockayne syndrome and other progeroid syndromes. Advances in experimental medicine and biology. 2008. PMID: 19181118
- Coin F, Oksenych V, Egly JM. Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair. Molecular cell. 2007. PMID: 17466626
- Oh KS, Imoto K, Boyle J. Influence of XPB helicase on recruitment and redistribution of nucleotide excision repair proteins at sites of UV-induced DNA damage. DNA repair. 2007. PMID: 17509950
- Oh KS, Khan SG, Jaspers NG. Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome. Human mutation. 2006. PMID: 16947863
- Riou L, Zeng L, Chevallier-Lagente O. The relative expression of mutated XPB genes results in xeroderma pigmentosum/Cockayne's syndrome or trichothiodystrophy cellular phenotypes. Human molecular genetics. 1999. PMID: 10332046
- Weeda G, Eveno E, Donker I. A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. American journal of human genetics. 1997. PMID: 9012405
- Weeda G, van Ham RC, Vermeulen W. A presumed DNA helicase encoded by ERCC-3 is involved in the human repair disorders xeroderma pigmentosum and Cockayne's syndrome. Cell. 1990. PMID: 2167179