Wikipedia

ERCC4

ERCC4is aproteindesignated asDNA repair endonuclease XPFthat in humans is encoded by theERCC4gene.Together withERCC1,ERCC4 forms the ERCC1-XPF enzyme complex that participates inDNA repairandDNA recombination.[5][6]

ERCC4
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesERCC4,ERCC11, FANCQ, RAD1, XPF, XFEPS, excision repair cross-complementation group 4, ERCC excision repair 4, endonuclease catalytic subunit
External IDsOMIM:133520;MGI:1354163;HomoloGene:3836;GeneCards:ERCC4;OMA:ERCC4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2072

50505

Ensembl

ENSG00000175595

ENSMUSG00000022545

UniProt

Q92889

Q9QZD4

RefSeq (mRNA)

NM_005236

NM_015769

RefSeq (protein)

NP_005227

NP_056584

Location (UCSC)Chr 16: 13.92 – 13.95 MbChr 16: 12.93 – 12.97 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Thenucleaseenzyme ERCC1-XPF cuts specific structures of DNA. Many aspects of these two gene products are described together here because they are partners during DNA repair. The ERCC1-XPF nuclease is an essential activity in the pathway of DNAnucleotide excision repair(NER). The ERCC1-XPF nuclease also functions in pathways to repairdouble-strand breaksin DNA, and in the repair of "crosslink" damage that harmfully links the two DNA strands.

Cells with disabling mutations inERCC4are more sensitive than normal to particular DNA damaging agents, includingultraviolet radiationand to chemicals that cause crosslinking between DNA strands. Genetically engineered mice withdisabling mutationsinERCC4also have defects in DNA repair, accompanied by metabolic stress-induced changes in physiology that result in premature aging.[7]Complete deletion ofERCC4is incompatible with viability of mice, and no human individuals have been found with complete (homozygous) deletion ofERCC4.Rare individuals in the human population harbor inherited mutations that impair the function ofERCC4.When the normal genes are absent, these mutations can lead to human syndromes, includingxeroderma pigmentosum,Cockayne syndromeandFanconi anemia.

ERCC1andERCC4are the human gene names andErcc1andErcc4are theanalogousmammalian gene names. Similar genes with similar functions are found in all eukaryotic organisms.

Gene

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The humanERCC4gene can correct the DNA repair defect in specific ultraviolet light (UV)-sensitive mutant cell lines derived from Chinese hamster ovary cells.[8]Multiple independent complementation groups of Chinese hamster ovary (CHO) cells have been isolated,[9]and this gene restored UV resistance to cells of complementation group 4. Reflecting this cross-species genetic complementation method, the gene was called "Excision repair cross-complementing 4"[10]

The humanERCC4gene encodes the XPF protein of 916 amino acids with a molecular mass of about 104,000 daltons.

Genes similar toERCC4with equivalent functions (orthologs) are found in other eukaryotic genomes. Some of the most studied gene orthologs includeRAD1in the budding yeastSaccharomyces cerevisiae,andrad16+in the fission yeastSchizosaccharomyces pombe.

Protein

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Figure 1: Diagram of XPF showing an inactive helicase domain, a nuclease domain and a helix-hairpin-helix domain

One ERCC1 molecule and one XPF molecule bind together, forming an ERCC1-XPF heterodimer which is the active nuclease form of the enzyme. In the ERCC1–XPF heterodimer, ERCC1 mediates DNA– and protein–protein interactions. XPF provides the endonuclease active site and is involved in DNA binding and additional protein–protein interactions.[8]

The ERCC4/XPF protein consists of two conserved areas separated by a less conserved region in the middle. The N-terminal area has homology to several conserved domains of DNA helicases belonging to superfamily II, although XPF is not a DNA helicase.[11]The C-terminal region of XPF includes the active site residues for nuclease activity.[12](Figure 1).

Most of the ERCC1 protein is related at the sequence level to the C terminus of the XPF protein.,[13]but residues in the nuclease domain are not present. A DNA binding "helix-hairpin-helix" domain at the C-terminus of each protein.

By primary sequence and protein structural similarity, the ERCC1-XPF nuclease is a member of a broader family of structure specific DNA nucleases comprising two subunits. Such nucleases include, for example, the MUS81-EME1 nuclease.

Structure-specific nuclease

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Figure 2: DNA substrates of ERCC1-XPF nuclease

The ERCC1–XPF complex is a structure-specific endonuclease. ERCC1-XPF does not cut DNA that is exclusively single-stranded or double-stranded, but it cleaves the DNA phosphodiester backbone specifically at junctions between double-stranded and single-stranded DNA. It introduces a cut in double-stranded DNA on the 5′ side of such a junction, about two nucleotides away[14](Figure 2).This structure-specificity was initially demonstrated for RAD10-RAD1, the yeast orthologs of ERCC1 and XPF.[15]

The hydrophobic helix–hairpin–helix motifs in the C-terminal regions of ERCC1 and XPF interact to promote dimerization of the two proteins.[16][17]There is no catalytic activity in the absence of dimerization. Indeed, although the catalytic domain is within XPF and ERCC1 is catalytically inactive, ERCC1 is indispensable for activity of the complex.

Several models have been proposed for binding of ERCC1–XPF to DNA, based on partial structures of relevant protein fragments at atomic resolution.[16]DNA binding mediated by the helix-hairpin-helix domains of ERCC1 and XPF domains positions the heterodimer at the junction between double-stranded and single-stranded DNA.

Nucleotide excision repair (NER)

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During nucleotide excision repair, several protein complexes cooperate to recognize damaged DNA and locally separate the DNA helix for a short distance on either side of the site of a site of DNA damage. The ERCC1–XPF nuclease incises the damaged DNA strand on the 5′ side of the lesion.[14]During NER, the ERCC1 protein interacts with the XPA protein to coordinate DNA and protein binding.

DNA double-strand break (DSB) repair

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Mammalian cells with mutant ERCC1–XPF are moderately more sensitive than normal cells to agents (such as ionizing radiation) that cause double-stranded breaks in DNA.[18][19]Particular pathways of both homologous recombination repair and non-homologous end-joining rely on ERCC1-XPF function.[20][21]The relevant activity of ERCC1–XPF for both types of double-strand break repair is the ability to remove non-homologous 3′ single-stranded tails from DNA ends before rejoining. This activity is needed during a single-strand annealing subpathway of homologous recombination. Trimming of 3’ single-stranded tails is also needed in a mechanistically distinct subpathway of non-homologous end-joining, independent of the Ku proteins[22][19]Homologous integration of DNA, an important technique for genetic manipulation, is dependent on the function of ERCC1-XPF in the host cell.[23]

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Mammalian cells carrying mutations in ERCC1 or XPF are especially sensitive to agents that cause DNA interstrand crosslinks (ICL)[24]Interstrand crosslinks block the progression of DNA replication, and structures at blocked DNA replication forks provide substrates for cleavage by ERCC1-XPF.[20][25]Incisions may be made on either side of the crosslink on one DNA strand to unhook the crosslink and initiate repair. Alternatively, a double-strand break may be made in the DNA near the ICL, and subsequent homologous recombination repair my involve ERCC1-XPF action. Although not the only nuclease involved, ERCC1–XPF is required for ICL repair during several phases of the cell cycle.[26][27]

Clinical significance

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Xeroderma pigmentosum (XP)

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Some individuals with the rare inherited syndromexeroderma pigmentosumhave mutations in ERCC4. These patients are classified as XP complementation group F (XP-F). Diagnostic features of XP are dry scaly skin, abnormal skin pigmentation in sun-exposed areas and severe photosensitivity, accompanied by a great than 1000-fold increased risk of developing UV radiation-induced skin cancers.[5]

Cockayne syndrome (CS)

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Most XP-F patients show moderate symptoms of XP, but a few show additional symptoms of Cockayne syndrome.[28]Cockayne syndrome (CS) patients exhibit photosensitivity, and also exhibit developmental defects and neurological symptoms.[5][7]

Mutations in the ERCC4 gene can result in the very rare XF-E syndrome.[29]These patients have characteristics of XP and CS, as well as additional neurologic, hepatobiliary, musculoskeletal and hematopoietic symptoms.

Fanconi anemia

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Several human patients with symptoms of Fanconi anemia (FA) have causative mutations in the ERCC4 gene. Fanconi anemia is a complex disease, involving major hematopoietic symptoms. A characteristic feature of FA is the hypersensitivity to agents that cause interstrand DNA crosslinks. FA patients with ERCC4 mutations have been classified as belonging to Fanconi anemia complementation group Q (FANCQ).[28][30]

ERCC4 (XPF) in the normalcolon

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Sequential sections of the samecolon cryptwithimmunohistochemicalstaining (brown) showing normal high expression of DNA repair proteinsPMS2(A),ERCC1(B) and ERCC4 (XPF) (C). This crypt is from the biopsy of a 58-year-old male patient who never had colonicneoplasiaand the crypt has high expression of these DNA repair proteins in absorptive cell nuclei throughout most of the crypt. Note that PMS2 and ERCC4 (XPF) expression (in panels A and C) are each reduced or absent in thenucleiof cells at the top of the crypt and within the surface of the coloniclumenbetween crypts. Original image, also in a publication.[31]

ERCC4 (XPF) is normally expressed at a high level in cellnucleiwithin the inner surface of thecolon(see image, panel C). The inner surface of the colon is lined with simple columnarepitheliumwithinvaginations.The invaginations are calledintestinal glandsor colon crypts. The colon crypts are shaped like microscopic thick walled test tubes with a central hole down the length of the tube (the cryptlumen). Crypts are about 75 to 110 cells long. DNA repair, involving high expression of ERCC4 (XPF), PMS2 and ERCC1 proteins, appears to be very active in colon crypts in normal, non-neoplasticcolon epithelium.

Cells are produced at the crypt base and migrate upward along the crypt axis before being shed into the coloniclumendays later.[32]There are 5 to 6stem cellsat the bases of the crypts.[32]There are about 10 million crypts along the inner surface of the average humancolon.[31]If thestem cellsat the base of the crypt express ERCC4 (XPF), generally all several thousand cells of the crypt will also express ERCC4 (XPF). This is indicated by the brown color seen by immunostaining of ERCC4 (XPF) in almost all the cells in the crypt in panel C of the image in this section. A similar expression of PMS2 and ERCC1 occurs in the thousands of cells in each normal colonic crypt.

The tissue section in the image shown here was alsocounterstainedwithhematoxylinto stain DNA in nuclei a blue-gray color. Nuclei of cells in thelamina propria,cells which are below and surround the epithelial crypts, largely show hematoxylin blue-gray color and have little expression of PMS2, ERCC1 or ERCC4 (XPF). In addition, cells at the very tops of the crypts stained for PMS2 (panel A) or ERCC4 (XPF) (panel C) have low levels of these DNA repair proteins, so that such cells show the blue-gray DNA stain as well.[31]

ERCC4 (XPF) deficiency in the colon epithelium adjacent to and within cancers

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Sequential sections of a segment ofcolonepitheliumnear acolorectal cancershowing reduced or absent expression ofPMS2(A),ERCC1(B) and ERCC4 (C) in the colon crypts. This tissue segment is from ahistologicallynormal area of a colon resection of a male patient who had anadenocarcinomain the sigmoid colon. For PMS2 (A), there is absent expression in cell nuclei of the crypt body, the crypt neck and the coloniclumensurface for all epithelial cells. For ERCC1 (B), there is reduced expression in most of the cell nuclei of the crypts, but there is high expression in cell nuclei at the neck of the crypts and in the adjacent coloniclumensurface. For ERCC4 (XPF) (C), there is absent expression in most of the cell nuclei of the crypts and in the colonic lumen in this area of tissue, but detectable expression at the neck of some crypts. The reductions or absence of expression of these DNA repair genes in this tissue appears to be due toepigenetic repression.[31]Original image, also in a publication.[31]

ERCC4 (XPF) is deficient in about 55% of colon cancers, and in about 40% of the colon crypts in the epithelium within 10 cm adjacent to the cancers (in thefield defectsfrom which the cancers likely arose).[31]When ERCC4 (XPF) is reduced in colonic crypts in a field defect, it is most often associated with reduced expression of DNA repair enzymes ERCC1 and PMS2 as well, as illustrated in the image in this section. Deficiencies in ERCC1 (XPF) in colon epithelium appear to be due toepigeneticrepression.[31]A deficiency of ERCC4 (XPF) would lead to reduced repair of DNA damages. As indicated by Harper and Elledge,[33]defects in the ability to properly respond to and repair DNA damage underlie many forms of cancer. The frequent epigenetic reduction in ERCC4 (XPF) in field defects surrounding colon cancers as well as in cancers (along with epigenetic reductions in ERCC1 and PMS2) indicate that such reductions may often play a central role in progression to colon cancer.

Although epigenetic reductions in ERCC4 (XPF) expression are frequent in human colon cancers, mutations in ERCC4 (XPF) are rare in humans.[34]However, a mutation in ERCC4 (XPF) causes patients to be prone to skin cancer.[34]An inherited polymorphism in ERCC4 (XPF) appears to be important in breast cancer as well.[35]These infrequent mutational alterations underscore the likely role of ERCC4 (XPF) deficiency in progression to cancer.

Notes

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References

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