Alternative titles; symbols
HGNC Approved Gene Symbol: ERCC8
SNOMEDCT: 890433006;
Cytogenetic location: 5q12.1 Genomic coordinates (GRCh38) : 5:60,866,454-60,945,070 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q12.1 | Cockayne syndrome, type A | 216400 | Autosomal recessive | 3 |
| UV-sensitive syndrome 2 | 614621 | Autosomal recessive | 3 |
The ERCC8 gene is part of the nucleotide excision repair (NER) pathway, a complex system that eliminates a broad spectrum of structural DNA lesions, including ultraviolet (UV)-induced cyclobutane pyrimidine dimers, bulky chemical adducts, and DNA cross-links. One of the NER pathways preferentially repairs lesions on the transcribed strand of active genes; this process occurs more rapidly than repairs on nontranscribed strands that are part of overall genome repair (Troelstra et al., 1992).
Henning et al. (1995) cloned the human CKN1 gene, which they called CSA, by functional complementation of cells derived from patients with Cockayne syndrome A (CSA; 216400). They found that the CSA cDNA uniquely and specifically corrected UV sensitivity in CSA cells. The predicted 396-amino acid protein has a calculated molecular mass of approximately 44 kD and contains a WD repeat (WD40 repeat) domain as reviewed by Neer et al. (1994). In vitro translated CSA protein specifically interacted with the CSB (ERCC6; 609413) protein and p44 protein (GTF2H2; 601748), a subunit of the RNA polymerase II basal transcription factor TFIIH (see also 189972). These observations, coupled with the observation that the amino acid sequence of the predicted CSB polypeptide is homologous with a component of the yeast Swi/Snf transcriptional activation complex, suggested that Cockayne syndrome cells are defective in RNA polymerase II transcription.
By Southern blot hybridization in human/rodent hybrid cell DNA, Henning et al. (1995) mapped the CSA gene to chromosome 5.
Damage to actively transcribed DNA is preferentially repaired by the transcription-coupled repair (TCR) system, which requires RNA polymerase II (pol II). Bregman et al. (1996) demonstrated that a fraction of the large subunit of pol II (POL2R; 180660) was ubiquitinated after exposing cells to UV-radiation or cisplatin but not several other DNA-damaging agents. This novel covalent modification of POL2R occurred within 15 minutes of exposing cells to UV-radiation and persisted for about 8 to 12 hours. Ubiquitinated POL2R was also phosphorylated on the C-terminal domain. UV-induced ubiquitination of POL2R was deficient in fibroblasts from persons with either Cockayne syndrome A or B (133540). In both of these disorders, transcription-coupled repair is disrupted. UV-induced ubiquitination of POL2R could be restored by introducing cDNA constructs encoding the CSA or CSB genes, respectively, into CSA or CSB fibroblasts. These results suggested that ubiquitination of POL2R plays a role in the recognition and/or repair of damage to actively transcribed genes. Alternatively, these findings may reflect a role played by the CSA and CSB gene products in transcription, a possibility that had been suggested on other grounds.
Van Gool et al. (1997) noted that there is evidence that basic metabolic processes within the cell are intimately linked and influenced by one another. One such link is the close interplay between nucleotide excision DNA repair and transcription, as illustrated both by the preferential repair of the transcribed strand of active genes (TCR) and by the distinct dual involvement of proteins in both processes. In E. coli, 1 protein, the transcription repair-coupling factor, accomplishes the dual function. On the basis of experimental observations, van Gool et al. (1997) suggested that the situation in eukaryotes is more complex, involving dual functionality of multiple proteins. They suggested that Cockayne syndrome may represent a defect in TCR.
By immunoprecipitation analysis of HeLa cells, Groisman et al. (2003) identified DDB2 (600811) and CSA as components of similar but distinct protein complexes. Both DDB2 and CSA interacted with DDB1 (600045), a component of both complexes. Cullin-4A (CUL4A; 603137), ROC1 (RBX1; 603814), and all the subunits of the COP9 signalosome (e.g., COPS2; 604508) were also present in both complexes. Following UV irradiation, the DDB2 complex bound tightly to chromatin in a UV-dependent manner and initiated global genome repair, whereas the CSA complex bound to RNA polymerase II and initiated TCR. The COP9 signalosome in each complex differentially regulated cullin-based ubiquitin ligase activity in response to UV irradiation.
Cockayne Syndrome A
Henning et al. (1995) identified mutations in the ERCC8 gene in CSA cDNAs of all CSA cell lines examined, including an identical mutation in 2 CSA sibs (609412.0001).
In a cell line from an 11-year-old girl with CSA, Cao et al. (2004) identified compound heterozygosity for a nonsense mutation (E13X; 609412.0003) and a missense mutation (A205P; 609412.0005) in the ERCC8 gene.
In a cell line from a patient with CSA, Ridley et al. (2005) identified compound heterozygosity for an E13X mutation and a novel missense mutation (A160V; 609412.0004) in the ERCC8 gene.
Bertola et al. (2006) analyzed the ERCC8 gene in 8 patients from 6 Brazilian families with typical CSA and identified homozygosity or compound heterozygosity for ERCC8 mutations in all of them. The authors stated that there was no obvious genotype/phenotype correlation across the mutation spectrum.
UV-Sensitive Syndrome 2
In a 15-year-old French girl with UV-sensitive syndrome-2 (UVSS2; 614621), Nardo et al. (2009) identified a homozygous mutation in the ERCC8 gene (W361C; 609412.0006). She had sun sensitivity and freckling, but no other abnormalities. Patient-derived fibroblasts showed a reduced recovery of RNA synthesis after UV irradiation and a defective capacity to repair UV-induced damage on the transcribed strand of active genes, indicating a defect in transcription-coupled nucleotide excision repair (TC-NER). However, there was no hypersensitivity to reactive oxygen species, and UV-induced DNA repair synthesis and global genome NER (GG-NER) were normal. Nardo et al. (2009) hypothesized that the mild phenotype in this patient was due to the lack of cellular sensitivity to oxidative stress.
The article by Fousteri et al. (2006) regarding the function of CSB and CSA in TCR complex formation was retracted because an investigation at the Leiden University Medical Center concluded that 'unacceptable data manipulation' by one of the authors 'led to breaches of scientific integrity, making these results unreliable.'
In 2 sibs, born of consanguineous parents, with Cockayne syndrome A (216400), Henning et al. (1995) identified 2 deletions in the ERCC8 gene. One deletion removed 279 bp from the CKN1 coding region, starting at nucleotide 880 of their sequence and ending at nucleotide 1158. A second deletion of 81 bp in the CKN1 region started at nucleotide position 1078 and also ended at nucleotide position 1158. The fact that the deletions identified in both cDNAs from both sibs ended at the identical nucleotide positions strongly suggested to the authors that this nucleotide marks an exon/intron junction and the truncated cDNAs represent abnormally spliced products missing either 1 (81 bp) or 2 (279 bp) upstream exons. These abnormal splice products presumably derived from a homozygous mutation in a splice donor site. Neither deletion created a frameshift. Hence, the 2 abnormal transcripts potentially encode internally deleted proteins with predicted sizes of 303 and 369 amino acids.
In a cell line derived from a patient with Cockayne syndrome A (216400), Henning et al. (1995) identified a C-to-A transversion in the ERCC8 gene, resulting in a tyr322-to-ter (Y322X) substitution.
McDaniel et al. (1997) demonstrated that the Y322X mutation was present in homozygous state, using a strategy with general applicability. Somatic cell hybrids were established by fusing patient cells with mouse A9 cells. Screening with chromosome 5-specific polymorphic markers facilitated identification of hybrid clones bearing only 1 of the distinct CSA alleles. Sequencing a portion of the human CSA gene in a subset of these hybrids permitted monoallelic mutation analysis and confirmed the presence of the Y322X mutation in both alleles.
Khayat et al. (2010) analyzed the Y322X mutation in the Arab Christian population of northern Israel and found a carrier frequency of 6.79. Haplotype analysis as well as the high carrier frequency suggested that Y322X is an ancient founder mutation that may have originated in the Christian Lebanese community.
In a cell line from a patient with Cockayne syndrome A (216400), Cao et al. (2004) identified compound heterozygosity for 2 mutations in the ERCC8 gene: a G-to-T transversion, resulting in a glu13-to-ter (E13X) substitution, and A205P (609412.0005). The patient was an 11-year-old girl with photophobia, dwarfism, mental retardation, cataracts, retinopathy, and optic atrophy.
In a cell line from a patient with Cockayne syndrome A (216400), Ridley et al. (2005) identified compound heterozygosity for 2 mutations in the ERCC8 gene: a 479C-T transition, resulting in an ala160-to-val (A160V) substitution between the second and third WD40 repeats, and E13X (609412.0003). No CSA protein was detected in the cells.
In a cell line from a patient with Cockayne syndrome A (216400), Cao et al. (2004) identified compound heterozygosity for 2 mutations in the ERCC8 gene: a 649G-C transversion, resulting in an ala205-to-pro (A205P) substitution, and E13X (609412.0003).
In a 15-year-old French girl with UV-sensitive syndrome-2 (UVSS2; 614621), Nardo et al. (2009) identified a homozygous 1083G-T transversion in the ERCC8 gene, resulting in a trp361-to-cys (W361C) substitution within the last putative WD domain. Her unaffected mother was heterozygous for the mutation. Patient-derived fibroblasts showed a reduced recovery of RNA synthesis after UV irradiation and a defective capacity to repair UV-induced damage on the transcribed strand of active genes, indicating a defect in transcription-coupled nucleotide excision repair (TC-NER). However, there was no hypersensitivity to reactive oxygen species, and UV-induced DNA repair synthesis and global genome NER (GG-NER) were normal. Transfection of the construct expressing the mutant protein into normal cells caused a defect in RNA synthesis after UV irradiation. The patient presented at age 4 months with sun sensitivity manifest as easy sun burning and erythema. She had numerous freckles on her face and exposed areas of the neck, but no history or evidence of cutaneous tumors. Psychomotor development was normal. Nardo et al. (2009) hypothesized that the mild phenotype in this patient was due to the lack of cellular sensitivity to oxidative stress.
Bertola, D. R., Cao, H., Albano, L. M. J., Oliveira, D. P., Kok, F., Marques-Dias, M. J., Kim, C. A., Hegele, R. A. Cockayne syndrome type A: novel mutations in eight typical patients. J. Hum. Genet. 51: 701-705, 2006. [PubMed: 16865293] [Full Text: https://doi.org/10.1007/s10038-006-0011-7]
Bregman, D. B., Halaban, R., van Gool, A. J., Henning, K. A., Friedberg, E. C., Warren, S. L. UV-induced ubiquitination of RNA polymerase II: a novel modification deficient in Cockayne syndrome cells. Proc. Nat. Acad. Sci. 93: 11586-11590, 1996. [PubMed: 8876179] [Full Text: https://doi.org/10.1073/pnas.93.21.11586]
Cao, H., Williams, C., Carter, M., Hegele, R. A. CKN1 (MIM 216400): mutations in Cockayne syndrome type A and a new common polymorphism. J. Hum. Genet. 49: 61-63, 2004. [PubMed: 14661080] [Full Text: https://doi.org/10.1007/s10038-003-0107-2]
Cleaver, J. E., Thompson, L. H., Richardson, A. S., States, J. C. A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum. Mutat. 14: 9-22, 1999. [PubMed: 10447254] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)14:1<9::AID-HUMU2>3.0.CO;2-6]
Fousteri, M., Vermeulen, W., van Zeeland, A. A., Mullenders, L. H. F. Cockayne syndrome A and B proteins differentially regulate recruitment of chromatin remodeling and repair factors to stalled RNA polymerase II in vivo. Molec. Cell 23: 471-482, 2006. Note: Retraction: Molec. Cell 81: 5112 only, 2021. [PubMed: 16916636] [Full Text: https://doi.org/10.1016/j.molcel.2006.06.029]
Groisman, R., Polanowska, J., Kuraoka, I., Sawada, J., Saijo, M., Drapkin, R., Kisselev, A. F., Tanaka, K., Nakatani, Y. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113: 357-367, 2003. [PubMed: 12732143] [Full Text: https://doi.org/10.1016/s0092-8674(03)00316-7]
Henning, K. A., Li, L., Iyer, N., McDaniel, L. D., Reagan, M. S., Legerski, R., Schultz, R. A., Stefanini, M., Lehmann, A. R., Mayne, L. V., Friedberg, E. C. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Cell 82: 555-564, 1995. [PubMed: 7664335] [Full Text: https://doi.org/10.1016/0092-8674(95)90028-4]
Khayat, M., Hardouf, H., Zlotogora, J., Shalev, S. A. High carriers frequency of an apparently ancient founder mutation p.Tyr322X in the ERCC8 gene responsible for Cockayne syndrome among Christian Arabs in northern Israel. Am. J. Med. Genet. 152A: 3091-3094, 2010. [PubMed: 21108394] [Full Text: https://doi.org/10.1002/ajmg.a.33746]
McDaniel, L. D., Legerski, R., Lehmann, A. R., Friedberg, E. C., Schultz, R. A. Confirmation of homozygosity for a single nucleotide substitution mutation in a Cockayne syndrome patient using monoallelic mutation analysis in somatic cell hybrids. Hum. Mutat. 10: 317-321, 1997. [PubMed: 9338586] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)10:4<317::AID-HUMU8>3.0.CO;2-D]
Nardo, T., Oneda, R., Spivak, G., Vaz, B., Mortier, L., Thomas, P., Orioli, D., Laugel, V., Stary, A., Hanawalt, P. C., Sarasin, A., Stefanini, M. A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage. Proc. Nat. Acad. Sci. 106: 6209-6214, 2009. [PubMed: 19329487] [Full Text: https://doi.org/10.1073/pnas.0902113106]
Neer, E. J., Schmidt, C. J., Nambudripad, R., Smith, T. F. The ancient regulatory-protein family of WD-repeat proteins. Nature 371: 297-300, 1994. Note: Erratum: Nature 371: 812 only, 1994. [PubMed: 8090199] [Full Text: https://doi.org/10.1038/371297a0]
Ridley, A. J., Colley, J., Wynford-Thomas, D., Jones, C. J. Characterisation of novel mutations in Cockayne syndrome type A and xeroderma pigmentosum group C subjects. J. Hum. Genet. 50: 151-154, 2005. [PubMed: 15744458] [Full Text: https://doi.org/10.1007/s10038-004-0228-2]
Troelstra, C., van Gool, A., de Wit, J., Vermeulen, W., Bootsma, D., Hoeijmakers, J. H. J. ERCC6, a member of a subfamily of putative helicases, is involved in Cockayne's syndrome and preferential repair of active genes. Cell 71: 939-953, 1992. [PubMed: 1339317] [Full Text: https://doi.org/10.1016/0092-8674(92)90390-x]
van Gool, A. J., van der Horst, G. T. J., Citterio, E., Hoeijmakers, J. H. J. Cockayne syndrome: defective repair of transcription? EMBO J. 16: 4155-4162, 1997. [PubMed: 9250659] [Full Text: https://doi.org/10.1093/emboj/16.14.4155]