Alternative titles; symbols
HGNC Approved Gene Symbol: ERCC5
SNOMEDCT: 36454001;
Cytogenetic location: 13q33.1 Genomic coordinates (GRCh38) : 13:102,846,032-102,875,995 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q33.1 | Cerebrooculofacioskeletal syndrome 3 | 616570 | Autosomal recessive | 3 |
| Xeroderma pigmentosum, group G | 278780 | Autosomal recessive | 3 | |
| Xeroderma pigmentosum, group G/Cockayne syndrome | 278780 | Autosomal recessive | 3 |
The human genes correcting DNA repair defects are termed excision repair cross-complementing, or ERCC, genes. A number appended to the symbol refers to the rodent complementary group that is corrected by the human gene. The ERCC5 gene corrects the excision repair deficiency of Chinese hamster ovary cell line UV135 of complementation group 5. The human ERCC5 gene product is a structure-specific endonuclease required for making the 3-prime incision during DNA nucleotide excision repair (NER). See also ERCC1 (126380), ERCC2 (126340), ERCC3 (133510), ERCC4 (133520), and ERCC6 (609413).
Mudgett and MacInnes (1990) isolated the complete human ERCC5 gene on overlapping cosmids. The functional gene was found to be 32 kb long.
MacInnes et al. (1993) isolated clones corresponding to the ERCC5 gene from human cDNA libraries. The deduced 1,186-residue protein has a molecular mass of 133 kD and shows sequence and structural similarity to yeast RAD2, which is involved in the nucleotide excision repair pathway. The human mRNA was 4.6 kb. Further analysis suggested that the protein is nuclear-located with highly conserved helix-loop-helix segments. Shiomi et al. (1994) isolated clones corresponding to both the mouse and human ERCC5 genes and confirmed that XPG and ERCC5 are identical.
Emmert et al. (2001) identified 6 alternatively spliced isoforms of the XPG gene.
Scherly et al. (1993) isolated frog and human cDNAs encoding proteins resembling RAD2. Alignment of these 3 polypeptides, together with 2 other RAD2-related proteins, demonstrated that their conserved sequences are largely confined to 2 regions. Expression of the human cDNA in vivo restored to normal the sensitivity to ultraviolet light and unscheduled DNA synthesis of lymphoblastoid cells from XP group G (278780), but not those from Cockayne syndrome group A (CSA; 216400). The XPG-complementing protein (XPGC) was generated from an mRNA of approximately 4 kb that was present in normal amounts in the XPG cell line.
O'Donovan et al. (1994) reported the isolation of full-length XPG as a soluble protein expressed from a recombinant baculovirus. The purified polypeptide corrected the DNA nucleotide excision repair defect of XPG cell extracts in vitro and acted as a magnesium-dependent single-stranded DNA endonuclease.
Harada et al. (1995) demonstrated that the mouse Xpg cDNA has a single long open reading frame predicted to encode a 1,170-residue protein with a molecular mass of 130.8 kD. The Xpg gene expressed a single 4.3-kb mRNA transcript at similar levels in 5 mouse tissues examined.
Emmert et al. (2001) determined that the human XPG gene contains 15 exons.
Using somatic cell hybrids between a UV-sensitive mutant mouse cell line and normal human lymphocytes, Hori et al. (1983) found that a gene on human chromosome 13 was able to compensate for an autosomal recessive DNA excision repair defect in mouse cell line Q31. Siciliano et al. (1987) and Thompson et al. (1987) assigned ERCC5 to chromosome 13 by study of somatic cell hybrids between normal human cells and Chinese hamster cells defective in UV-induced nucleotide excision repair (UV135, complementation group 5). Study of hybrid cells containing rearranged human chromosomes indicated that the ERCC5 locus is situated in the region 13q14-q34.
Gersen et al. (1989) used somatic cell hybrids containing fragments of chromosome 13 to localize ERCC5 to human chromosome 13q22-qter. By fluorescence in situ hybridization, Warburton et al. (1991) mapped the ERCC5 gene to 13q32-qter but also found a strong hybridization signal at 10q11 where ERCC6 is located.
By fluorescence in situ hybridization, Takahashi et al. (1992) mapped the ERCC5 gene to 13q32.3-q33.1. By the same method, Samec et al. (1994) assigned the XPG gene to 13q33.
By in situ hybridization and by molecular linkage analysis, Harada et al. (1995) mapped the mouse Xpg gene 2.3 cM proximal to the microsatellite locus D1Mit18 on the R-positive B band of chromosome 1. The rat homolog was localized to chromosome 9q22.3, which had been known to have a conserved linkage homology to mouse chromosome 1. The assignment of human XPG to chromosome 13q32.3-q33.1 represents an area where no conserved linkage homology to mouse chromosome 1 had previously been found.
O'Donovan and Wood (1993) found that the DNA repair deficiency of XPG cell extracts could be corrected by addition of protein fractions from normal cells and by mixing XPG cell extracts with extracts from different repair-defective cell lines, except from cells representing ERCC5 rodent mutants. XPG and group 5 correcting activities co-eluted after approximately 1,000-fold purification from HeLa cells. An antibody directed against a fragment of the XPG protein inhibited excision repair by normal cell extracts, and activity could be restored with an XPG/group 5 complementing fraction. These data suggested that XPG and ERCC5 are identical proteins. O'Donovan et al. (1994) showed that the XPG endonuclease cleaves the damaged DNA strand 3-prime to the lesion during nucleotide excision repair.
Habraken et al. (1994) expressed the XPG-encoded protein in Sf9 insect cells and purified it to homogeneity. They demonstrated that XPG is a single-strand specific DNA endonuclease, thus identifying the catalytic role of the protein in nucleotide excision repair. They suggested that XPG nuclease acts on the single-stranded region created as a result of the combined action of the XPB helicase and XPD helicase at the DNA damage site.
TFIIH (see 189972) is a multisubunit transcription factor complex involved in nucleotide excision repair. In humans, mutations in the TFIIH subunits XPD (126340) and XPB (133510), the counterparts of the yeast RAD3 and RAD25 genes, respectively, cause Cockayne syndrome, which is characterized by severe growth defects, mental retardation, and cachexia. In yeast studies, Habraken et al. (1996) found that RAD2 forms a stable subassembly with TFIIH, which they designated nucleotide excision repair factor-3 (NEF3). Association with TFIIH provided a means of targeting RAD2 to the damaged site, where its endonuclease activity would mediate the 3-prime incision. Habraken et al. (1996) speculated that mutations in XPB, XPD, and XPG that result in Cockayne syndrome all impair TFIIH function in a similar manner by resulting in a deficiency in the rate of elongation of certain transcripts.
Volker et al. (2001) described the assembly of the NER complex in normal and repair-deficient (xeroderma pigmentosum) human cells by employing a novel technique of local ultraviolet irradiation combined with fluorescent antibody labeling. The damage-recognition complex XPC (613208)-HR23B (RAD23B; 600062) appeared to be essential for the recruitment of all subsequent NER factors in the preincision complex, including transcription repair factor TFIIH. Volker et al. (2001) found that XPA (611153) associated relatively late, was required for anchoring of subsequent subunits, and appeared to be essential for activation of the endonuclease activity of XPG. These findings identified XPC as the earliest known NER factor in the reaction mechanism and supported a concept of sequential assembly of repair proteins at the site of damage rather than a preassembled 'repairosome.'
Lee et al. (2002) provided evidence that S. cerevisiae Rad2 is involved in promoting efficient RNA polymerase II transcription. Inactivation of Rad26, the S. cerevisiae counterpart of the human ERCC6 gene, also caused a deficiency in transcription, and a synergistic decline in transcription occurred in the absence of both the Rad2 and Rad26 genes. Growth was also retarded in Rad2-deletion and Rad26-deletion single mutant strains, and a very severe growth inhibition was seen in Rad2-deletion/Rad26-deletion double mutants.
Sarker et al. (2005) found that XPG interacted with elongating RNA polymerase II in HeLa cells and bound stalled ternary complexes in vitro both independently and cooperatively with ERCC6. XPG bound transcription-sized DNA bubbles, through 2 domains not required for incision, stimulated ERCC6 binding to DNA bubbles and enhanced the ATPase activity of ERCC6. Bound RNA polymerase II blocked bubble incision by XPG, but an ATP hydrolysis-dependent process involving TFIIH created access to the junction, allowing incision. Sarker et al. (2005) concluded that coordinated recognition of stalled transcription by XPG and ERCC6 initiates transcription-coupled repair, and that TFIIH-dependent remodeling of stalled RNA polymerase II without release may be sufficient to allow repair.
Ito et al. (2007) found that XPG forms a stable complex with TFIIH and that the complex was able to repair damaged DNA in an in vitro assay of NER using cell extracts from XPB, XPD, or XPG cells. A mutation in the XPG gene that lacked the C terminus (133530.0003) and was unable to bind TFIIH resulted in a severe phenotype with XPG/Cockayne syndrome, whereas a missense mutation (133530.0002) that retained the C terminus region and had the ability to bind TFIIH resulted in a milder XPG phenotype. Mutations in the XPG gene that disrupted the C terminal and prevented the association with TFIIH also resulted in the disassociation of CAK (CCNH; 601953) and XPD from TFIIH. Further in vitro studies showed that XPG cells were deficient in ligand-induced transactivation of nuclear receptors due to hypophosphorylation resulting from the disintegration of TFIIH subunits. Ito et al. (2007) suggested that defective transactivation of nuclear receptors may account for some of the variable phenotypic features associated with XPG/Cockayne syndrome, such as growth failure and hypogonadism. The findings indicated that XPG plays a role in the stabilization of TFIIH and in the regulation of gene expression.
Nouspikel and Clarkson (1994) found that 2 sibs with xeroderma pigmentosum complementation group G (XPG; 278780) were compound heterozygous for 2 point mutations in the ERCC5 gene (133530.0001; 133530.0002).
Lalle et al. (2002) found that the first 2 patients reported with XPG (Cheesbrough, 1978; Keijzer et al., 1979; Arlett et al., 1980) produced XPG protein with severely impaired endonuclease activity. Both patients were compound heterozygous for truncating mutations in the ERCC5 gene (133530.0009, 133530.0010) and another mutation (133530.0008 and 133530.0011, respectively). These cells, unlike those from xeroderma pigmentosum group G/Cockayne syndrome patients, were capable of limited transcription-coupled repair of oxidative lesions. Lalle et al. (2002) suggested that the residual ERCC5 activity in these patients was responsible for the absence of severe early-onset Cockayne syndrome symptoms.
Nouspikel et al. (1997) studied the nature of the molecular defect in the first 3 documented cases of combined XPG and Cockayne syndrome (see 278780) reported by Jaeken et al. (1989), Vermeulen et al. (1993), and Hamel et al. (1996). They found an unexpected common mutational pattern in the 3 patients with XPG/CS that was distinct from that found in 2 sibs with mild XPG without CS symptoms (Norris et al., 1987). Nouspikel et al. (1997) found that the 3 XPG/CS patients had mutations that were predicted to produce severely truncated XPG proteins. In contrast, 2 sib XPG patients without CS reported by Nouspikel and Clarkson (1994) were able to make full-length XPG, but had a mutation that inactivated its function in NER. The results suggested that XPG/CS mutations abolish interactions required for a second important XPG function and that it is the loss of this second function that leads to the CS clinical phenotype. (Note that Figure 6 of the report of Nouspikel et al. (1997) was retracted under a Voluntary Exclusion Agreement between one of the authors, Steven A. Leaden, and the U.S. Department of Health and Human Services. The other authors stated that the other findings and conclusions of the article were not challenged by retraction of Figure 6.)
Cleaver et al. (1999) reviewed mutations that had been described in the XPG gene.
Cerebrooculofacioskeletal Syndrome 3
In a boy, born of consanguineous Moroccan parents, with cerebrooculofacioskeletal syndrome-3 (COFS3; 616570) originally reported by Hamel et al. (1996), Nouspikel et al. (1997) identified a homozygous truncating mutation in the ERCC5 gene (133530.0003).
In 4 fetuses from a large consanguineous Pakistani kindred with COFS3, Drury et al. (2014) identified a homozygous truncating mutation in the ERCC5 gene (133530.0016) predicting the loss of the C terminus. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed.
Shiomi et al. (2004) created mice carrying mutations in the Xpg gene leading to C-terminal deletions in the protein. Mice homozygous for a mutation leading to deletion of the last 360 amino acids exhibited growth retardation and a shorter life span than controls, but they had a slightly milder CS phenotype than Xpg null mice. Mice homozygous for a mutation leading to deletion of the last 183 amino acids showed no growth abnormalities compared with wildtype mice.
Vermeij et al. (2016) reported that a dietary restriction of 30% tripled the median and maximal remaining lifespans of Ercc1 (126380) delta/- progeroid mice, strongly retarding numerous aspects of accelerated aging. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Ercc5 -/- mice, another DNA repair-deficient progeroid mouse that models Cockayne syndrome (see 278780), responded similarly. The dietary restriction response in Ercc1 delta/- mice closely resembled the effects of dietary restriction in wildtype animals. Notably, liver tissue from Ercc1 delta/- mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon also observed in several tissues aging normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of gamma-H2AX (601772) DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Vermeij et al. (2016) concluded that their findings established the Ercc1 delta/- mouse as a powerful model organism for health-sustaining interventions, revealed potential for reducing endogenous DNA damage, facilitated a better understanding of the molecular mechanism of dietary restriction, and suggested a role for counterintuitive dietary restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.
Lehmann et al. (1994) recommended that the final C in the XPGC symbol be omitted and the gene cited as XPG. Furthermore, they recommended that when an inactivating mutation in the ERCC5 gene is identified in an XPG patient, XPG should be used as the gene symbol.
Cooper et al. (1997) reported that oxidative damage, including thymine glycols, is removed by transcription-coupled repair in cells from normal individuals and from patients with xeroderma pigmentosum of complementation groups A (XPA; 278700), F (XPF; 278760), and G who have NER defects, but not from XPG patients who have severe Cockayne syndrome. Cooper et al. (2005) retracted the paper of Cooper et al. (1997), stating that the results were not valid as reported and that the overall integrity of the paper could not be supported by the presented results.
In lymphoblastoid cell lines derived from 2 sibs with xeroderma pigmentosum complementation group G (XPG; 278780), Nouspikel and Clarkson (1994) identified compound heterozygosity for 2 mutations in the ERCC5 gene: a 3075G-T transversion resulting in a glu960-to-ter (Q960X) substitution and a truncated protein of 959 amino acids, and A792V (133530.0002). In vitro functional expression studies showed that neither mutant protein was able to correct UV sensitivity.
In 2 sibs with xeroderma pigmentosum complementation group G (XPG; 278780), Nouspikel and Clarkson (1994) identified a 2572C-T transition in the ERCC5 gene, resulting in an ala792-to-val (A792V) substitution. The mutation was found in compound heterozygosity with Q960X (133530.0001). In vitro functional expression studies showed that neither mutant protein was able to correct UV sensitivity.
Ito et al. (2007) found that the A792V mutant protein, which contains an intact C terminus, was able to bind TFIIH in a manner similar to that of wildtype ERCC5, likely resulting in the milder phenotype.
In a patient with cerebrooculofacioskeletal syndrome-3 (COFS3; 616570) manifest as severe early-onset XPG/Cockayne syndrome reported by Hamel et al. (1996), Nouspikel et al. (1997) identified a homozygous 1-bp deletion (2972delT) in the ERCC5 gene, resulting in a frameshift after amino acid 925; another 55 amino acids unrelated to XPG would be added before the next in-frame stop codon. The child was born of first-cousin Moroccan parents and died at age 7 months.
Graham et al. (2001) referred to the case reported by Hamel et al. (1996) as one of COFS syndrome. The patient showed prenatal-onset growth deficiency, severe microcephaly, microphthalmia without cataracts, cleft palate, cutaneous photosensitivity, and brain atrophy without calcifications. Skin fibroblasts showed extreme cellular sensitivity to UV, comparable to that in classic xeroderma pigmentosum. Using in vitro studies, Ito et al. (2007) found that the mutant 2972delT protein, which lacked the C terminus, was unable to bind the TFIIH complex, likely resulting in the more severe phenotype.
In a Flemish girl with XPG/Cockayne syndrome (see 278780), Nouspikel et al. (1997) identified a homozygous 1-bp deletion within an AAA triplet at nucleotides 2170-2172, which resulted in a TGA stop codon after amino acid 659. Such a deletion was considered characteristic of a slippage error during DNA replication. The patient had psychomotor retardation, microcephaly, and was severely sunlight-sensitive with several pigmented cutaneous spots (Jaeken et al., 1989; Vermeulen et al., 1993). She died at 6.5 years of age.
In fibroblasts derived from a Flemish male with XPG/Cockayne syndrome (see 278780) Nouspikel et al. (1997) identified compound heterozygosity for 2 mutations in the ERCC5 gene: a 984C-T transition resulting in an arg263-to-ter (R263X) substitution and a severely truncated protein, and a 1-bp deletion (113530.0004) that had been identified in an unrelated Flemish girl. The 984C-T transition was located within a CpG dinucleotide and thus may have resulted from deamination of a 5-methylcytosine. The patient had extreme microcephaly, dysmorphism, and sun-sensitive skin with several pigmented spots. He died at age 20 months. The 2 patients were not known to be related, but possessed a very rare HLA haplotype in common.
In a patient with xeroderma pigmentosum complementation group G and neurologic involvement with features of Cockayne syndrome (see 278780) in infancy, Zafeiriou et al. (2001) identified compound heterozygosity for 2 mutations in the ERCC5 gene: a 526C-T transition resulting in a gln176-to-ter (Q176X) substitution, and P72H (133530.0007). Only a minor fraction of ERCC5 mRNA was encoded by the Q176X allele.
In a patient with XPG/Cockayne syndrome (see 278780), Zafeiriou et al. (2001) identified a 215C-A transversion in the ERCC5 gene, resulting in a pro72-to-his (P72H) substitution. This mutation was found in compound heterozygosity with Q176X (133530.0006). The P72H substitution was expected to seriously impair the 3-prime endonuclease function of XPG.
In the first patient reported with xeroderma pigmentosum complementation group G (XPG; 278780) (Cheesbrough, 1978; Keijzer et al., 1979), Lalle et al. (2002) identified compound heterozygosity for 2 mutations in the ERCC5 gene. One allele carried a 2573T-C transition, resulting in a leu858-to-pro (L858P) substitution within the evolutionarily conserved I region that is thought to form part of the XPG endonuclease active site (Constantinou et al., 1999). The other allele carried a 4-bp deletion (133530.0009).
In the first patient reported with xeroderma pigmentosum complementation group G (XPG; 278780) (Cheesbrough, 1978; Keijzer et al., 1979), Lalle et al. (2002) identified compound heterozygosity for 2 mutations in the ERCC5 gene: an L858P substitution (133530.0008), and a 4-bp deletion removing AGGA from nucleotide positions 1114 to 1117. The deletion created a frameshift resulting in a truncated protein of 376 amino acids.
In a patient with xeroderma pigmentosum complementation group G (XPG; 278780) reported by Arlett et al. (1980), Lalle et al. (2002) identified deletion of an adenosine from a stretch of 4 adenosines at nucleotides 1491 to 1494 of the ERCC5 gene. The resulting frameshift generated a truncated protein of 521 amino acids, the last 23 being unrelated to XPG. The other allele carried a deletion of an adenosine in a stretch of 9 adenosines (133530.0011).
In a patient with xeroderma pigmentosum complementation group G (XPG; 278780), Lalle et al. (2002) identified compound heterozygosity for 2 small deletions in the ERCC5 gene. One allele had deletion of an adenosine at position 1491 (133530.0010), and the other had a deletion of an adenosine in a stretch of 9 adenosines at positions 2743 to 2751 of the ERCC5 gene. The authors designated this mutation 2751delA. An intron whose splice donor and acceptor sites are noncanonical is located between the deletion and the termination codon resulting from the frameshift; the mutation caused a minor alternative splicing event that removed the first 2 nucleotides of the following exon (2880-2881del). In this patient, the combination of this splicing event and the single-nucleotide deletion at position 2751 was predicted to restore the reading frame and thereby generate an almost full-length XPG protein of 1,185, instead of 1,186, amino acids. Such a protein would contain an internal stretch of 44 unrelated amino acids.
Emmert et al. (2002) reported a mildly affected 14-year-old Caucasian female with xeroderma pigmentosum complementation group G (XPG; 278780) who was compound heterozygous for 2 mutations in the ERCC5 gene: an early stop codon (Q136X; 133530.0013) and a 2817G-A transition resulting in an ala874-to-thr (A874T) substitution. The A874T mutant protein showed residual ability to complement XPG cells in vitro. The observations agreed with earlier studies demonstrating that XPG patients who retain residual functional activity in 1 allele can have mild clinical features without neurologic abnormalities. The patient had sun sensitivity but no neurologic abnormalities.
In a mildly affected girl with xeroderma pigmentosum complementation group G (XPG; 278780), Emmert et al. (2002) identified compound heterozygosity for 2 mutations in the ERCC5 gene: a 603C-T transition in exon 4 resulting in a gln136-to-ter (Q136X) substitution and A874T (133530.0012). The A874T mutant protein retained residual activity.
In 2 sibs, born of unrelated Brazilian parents, with xeroderma pigmentosum complementation group G (XPG; 278780), Soltys et al. (2013) identified compound heterozygosity for 2 mutations in the ERCC5 gene: an 83C-A transversion, resulting in an ala28-to-asp (A28D) substitution at the N-endonucleolytic site, and a 2904G-C transversion, resulting in a trp968-to-cys (W968C; 133530.0015) substitution in the protein domain believed to be responsible for protein-DNA contact. In vitro functional expression studies showed that both mutant proteins were able to partially restore activity in cells lacking ERCC5 in response to UV light, but not as well as the wildtype protein. Both mutant proteins showed activity comparable to wildtype in response to oxidative stress. The patients had a relatively mild form of the disorder, with photosensitivity first apparent in infancy, but had no history of skin cancer or skin cancer precursor lesions up to ages 22 and 17 years, respectively. Patient cells showed a strong DNA repair defect in response to UV light, but not in response to oxidative stress. Soltys et al. (2013) suggested that more severe ERCC5 defects that also impair the response to oxidative stress-induced injury, usually truncating mutations, (see, e.g., 133530.0003) are associated with the more severe phenotype observed in Cockayne syndrome.
For discussion of the trp968-to-cys (W968C) mutation in the ERCC5 gene that was found in compound heterozygous state in patients with xeroderma pigmentosum complementation group G (XPG; 278780) by Soltys et al. (2013), see 133530.0014.
In 4 fetuses, born of consanguineous Pakistani parents, with cerebrooculofacioskeletal syndrome-3 (COFS3; 616570), Drury et al. (2014) identified a homozygous 1-bp duplication (c.2766dupA) in exon 13 of the ERCC5 gene, resulting in a frameshift and premature termination (Leu923ThrfsTer7) that would eliminate the C terminus. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed.
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