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ERCC5
ERCC excision repair 5, endonuclease
ERCC5 is located on the long (q) arm of chromosome 13, at band 13q33.1. Arm ratio per GRCh38 - banding schematic.
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Overview
ERCC5, also known as excision repair cross-complementing group 5, encodes an endonuclease protein with a central role in maintaining genomic integrity. The gene spans chromosome 13q33.1 and produces a 1186-amino-acid enzyme that participates in nucleotide excision repair, one of the principal pathways cells use to identify and remove bulky DNA lesions induced by ultraviolet radiation and genotoxic chemicals.
Biallelic pathogenic variants in ERCC5 are associated with autosomal recessive DNA repair disorders, including xeroderma pigmentosum complementation group G and a severe form of Cockayne syndrome. Individuals with these conditions experience profound sensitivity to sunlight, developmental abnormalities, and a substantially increased predisposition to skin malignancies. Because ERCC5 function is critical across multiple organ systems, loss of its activity can result in diverse clinical presentations ranging from isolated skin cancer susceptibility to multisystem neurological decline.
What the gene does
The ERCC5 protein functions as a structure-specific endonuclease within the nucleotide excision repair machinery, cleaving damaged DNA strands to enable excision of nucleotide lesions. During repair, a multiprotein complex recognises distortions in the DNA helix caused by ultraviolet-induced pyrimidine dimers or chemical adducts. ERCC5 is recruited to the damage site and makes an incision on the 3' side of the lesion, working in concert with the ERCC1-ERCC4 complex, which cuts on the 5' side. This dual incision releases a short oligonucleotide fragment containing the damaged bases, allowing DNA polymerases to fill the resulting gap using the undamaged strand as a template.
Beyond its endonuclease activity, ERCC5 interacts with several regulatory proteins that coordinate the repair response. The protein binds to proliferating cell nuclear antigen, helping to orchestrate DNA synthesis during the final stages of repair, and associates with ERCC6, a chromatin remodelling factor involved in transcription-coupled repair. These interactions ensure that lesions blocking RNA polymerase progression are preferentially repaired, safeguarding active genes from mutation accumulation. Loss of ERCC5 function impairs both global genome repair and transcription-coupled repair, rendering cells unable to efficiently remove helix-distorting damage.
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Chromosome location
ERCC5 is located at chromosomal band 13q33.1 on the long arm of chromosome 13. The gene comprises multiple exons encoding a full-length transcript that produces the 1186-amino-acid ERCC5 protein. This genomic region has been mapped through linkage studies in families affected by nucleotide excision repair deficiencies, establishing 13q33.1 as the definitive locus for ERCC5-related disorders.
Protein structure
The ERCC5 protein exhibits a modular architecture with functionally distinct regions distributed across its 1186-residue length. The N-domain, spanning amino acids 1 to 78, contains a DNA-binding region (residues 31-67) thought to engage undamaged single-strand DNA within the repair bubble formed during excision. A spacer region extends from residue 79 to 785, within which lies a ubiquitin-binding motif (UBM domain, residues 180-215) and several disordered segments (residues 306-342, 354-385, 404-473, 510-533, and 667-724) that may confer flexibility for protein-protein interactions.
The I-domain, positioned at residues 786 to 881, houses additional DNA-binding elements: a region binding undamaged single-strand DNA (residues 820-836) and a helix-2turn-helix motif (H2TH, residues 848-880) that recognises double-stranded DNA structures. A further double-stranded DNA-binding site maps to residues 912-918. The C-terminal region mediates critical interactions, with residues 981-1009 binding proliferating cell nuclear antigen (PCNA) to coordinate repair synthesis, and residues 1011-1186 interacting with ERCC6 (also known as CSB) to facilitate transcription-coupled repair. This domain organisation enables ERCC5 to simultaneously recognise damaged DNA, execute endonuclease cleavage, and recruit downstream repair factors.
Key variants
Pathogenic variants in ERCC5 typically result in loss of endonuclease function, compromising the cell's ability to excise damaged nucleotides. Most disease-causing changes are nonsense or frameshift variants that introduce premature stop codons, leading to truncated proteins lacking essential catalytic or DNA-binding domains. Missense variants affecting conserved residues within the I-domain or H2TH motif can also abolish enzymatic activity. Because ERCC5-related conditions follow autosomal recessive inheritance, affected individuals carry pathogenic variants on both gene copies, whilst heterozygous carriers with one functional allele generally remain asymptomatic.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in ERCC5 cause xeroderma pigmentosum complementation group G and a severe early-onset form of Cockayne syndrome. Xeroderma pigmentosum is characterised by extreme photosensitivity, freckling in sun-exposed areas during early childhood, and a more than 1000-fold increased risk of skin cancers, including melanoma and squamous cell carcinoma, often appearing before age 10. Cockayne syndrome associated with ERCC5 variants presents with growth failure, progressive neurodegeneration, microcephaly, and skeletal abnormalities, alongside the photosensitivity seen in xeroderma pigmentosum. The phenotypic spectrum reflects the degree of residual ERCC5 activity, with null variants generally producing the most severe multisystem presentations.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ERCC5 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
ERCC5 is included on multiple NHS Genomic Medicine Service gene panels reflecting its role in hereditary cancer predisposition and developmental disorders. The gene holds green (high-evidence) status on the Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome panel (R227), Adult solid tumours cancer susceptibility, Childhood solid tumours cancer susceptibility, and Childhood solid tumours (R359) panels. ERCC5 also appears on panels for Intellectual disability (R29), Fetal anomalies (R21), and Arthrogryposis (R83), underscoring the gene's pleiotropic effects when repair function is lost. This broad panel representation ensures that pathogenic ERCC5 variants are reportable across paediatric, cancer, and prenatal genomic testing pathways within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ERCC5 gene do?
ERCC5 encodes an endonuclease enzyme that cuts damaged DNA during nucleotide excision repair, enabling cells to remove and replace nucleotides altered by ultraviolet light or chemical exposure. This process is essential for preventing mutations that can lead to cancer or cellular dysfunction.
How are ERCC5 variants inherited?
ERCC5-related conditions follow autosomal recessive inheritance, meaning an affected individual inherits a pathogenic variant from each parent. Carriers with one pathogenic variant and one functional copy typically do not develop symptoms.
Why is ERCC5 on multiple NHS cancer panels?
Pathogenic ERCC5 variants markedly elevate skin cancer risk due to impaired DNA repair, warranting inclusion on both adult and childhood cancer susceptibility panels. The gene also appears on developmental disorder panels because loss of ERCC5 function can cause neurological and growth abnormalities in addition to cancer predisposition.