DNA repair protein XRCC4
XRCC4 | |||
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Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process |
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Sources:Amigo / QuickGO |
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UniProt | |||||||||
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RefSeq (protein) |
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Location (UCSC) | Chr 5: 83.08 – 83.35 Mb | Chr 13: 89.92 – 90.24 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
DNA repair protein XRCC4 also known as X-ray repair cross-complementing protein 4 or XRCC4 is a
NHEJ requires two main components to achieve successful completion. The first component is the cooperative binding and
Since XRCC4 is the key protein that enables interaction of LigIV to damaged DNA and therefore ligation of the ends, mutations in the XRCC4 gene were found to cause embryonic lethality in mice and developmental inhibition and immunodeficiency in humans.[9] Furthermore, certain mutations in the XRCC4 gene are associated with an increased risk of cancer.[10]
Double strand breaks
DSBs are mainly caused by free radicals generated from ionizing radiation in the environment and from by-products released continually during cellular metabolism. DSBs that are not efficiently repaired may result in the loss of important protein coding genes and regulatory sequences required for gene expression necessary for the life of a cell.[8][11] DSBs that cannot rely on a newly copied sister chromosome generated by DNA replication to fill in the gap will go into the NHEJ pathway. This method of repair is essential as it is a last resort to prevent loss of long stretches of the chromosome.[8][12] NHEJ is also used to repair DSBs generated during V(D)J recombination when gene regions are rearranged to create the unique antigen binding sites of antibodies and T-cell receptors.[8]
Sources of DNA damage
DNA damage occurs very frequently and is generated from exposure to a variety of both exogenous and endogenous genotoxic sources.
Consequences of DSBs
There are many types of DNA damage, but DSBs, in particular, are the most harmful as both strands are completely disjointed from the rest of the chromosome. If an efficient repair mechanism does not exist, the ends of the DNA can eventually degrade, leading to a permanent loss of sequence.[8] A double-stranded gap in DNA will also prevent replication from proceeding, resulting in an incomplete copy of that specific chromosome, targeting the cell for apoptosis. As with all DNA damage, DSBs can introduce new mutations that can ultimately lead to cancer.[8][11]
DSB repair methods
There are two methods for repairing DSBs depending on when the damage occurs during mitosis.[6] If the DSB occurs after DNA replication has completed proceeding S phase of the cell cycle, the DSB repair pathway will use homologous recombination by pairing with the newly synthesized daughter strand to repair the break. However, if the DSB is generated prior to synthesis of the sister chromosome, then the template sequence that is required will be absent.[8] For this circumstance, the NHEJ pathway provides a solution for repairing the break and is the main system used to repair DSBs in humans and multicellular eukaryotes.[6][8][9][13] During NHEJ, very short stretches of complementary DNA, 1 bp or more at a time, are hybridized together, and the overhangs are removed. As a result, this specific region of the genome is permanently lost and the deletion can lead to cancer and premature aging.[8][12]
Properties
Gene and protein
The human XRCC4
Structure
XRCC4 | |||||||||
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Identifiers | |||||||||
Symbol | XRCC4 | ||||||||
SCOP2 | 1fu1 / SCOPe / SUPFAM | ||||||||
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XRCC4 protein is a tetramer that resembles the shape of a dumbbell containing two globular ends separated by a long, thin stalk. The tetramer is composed of two dimers, and each dimer is made up of two similar subunits. The first subunit (L) contains amino acid residues 1 – 203 and has a longer stalk than the second subunit (S) which contains residues 1 – 178.
The globular
The two helical stalks between subunits L and S intertwine with a single left-handed crossover into a
Post-translational modifications
In order for XRCC4 to be sequestered from the
Interactions
Upon generation of a DSB, Ku proteins will move through the cytoplasm until they find the site of the break and bind to it.
Mechanism
NHEJ
The process of NHEJ involves XRCC4 and a number of tightly coupled proteins acting in concert to repair the DSB. The system begins with the binding of one heterodimeric protein called Ku70/80 to each end of the DSB to maintain them close together in preparation for
V(D)J recombination
V(D)J recombination is the rearrangement of multiple, distinct
Pathology
Recent studies have shown an association between XRCC4 and potential susceptibility to a variety of pathologies. The most frequently observed linkage is between XRCC4 mutations and susceptibility to cancers such as bladder cancer, breast cancer, and lymphomas. Studies have also pointed to a potential linkage between XRCC4 mutation and endometriosis. Autoimmunity is also being studied in this regard. Linkage between XRCC4 mutations and certain pathologies may provide a basis for diagnostic biomarkers and, eventually, potential development of new therapeutics.
Cancer susceptibility
XRCC4
Senescence
Declining ability to repair DNA double-strand breaks by
Autoimmunity
Based on the findings that (1) several polypeptides in the NHEJ pathway are "potential targets of autoantibodies" and (2) "one of the autoimmune epitopes in XRCC4 coincides with a sequence that is a nexus for radiation-induced regulatory events", it has been suggested that exposure to DNA double-strand break-introducing agents "may be one of the factors" mediating autoimmune responses.[27][28]
Endometriosis susceptibility
There has been speculation that "XRCC4 codon 247*A and XRCC4 promoter -1394*T related genotypes and alleles... might be associated with higher endometriosis susceptibilities and pathogenesis".[29]
Potential use as a cancer biomarker
In view of the possible associations of XRCC4 polymorphisms with risk of cancer susceptibility (see discussion above), XRCC4 could be used as a biomarker for cancer screening, particularly with respect to prostate cancer, breast cancer, and bladder cancer.[20] In fact, XRCC4 polymorphisms were specifically identified as having the potential to be novel useful markers for "primary prevention and anticancer intervention" in the case of urothelial bladder cancer.[20]
Radiosensitization of tumor cells
In view of the role of XRCC4 in
Potential role in therapeutics
There has been discussion in the literature concerning the potential role of XRCC4 in the development of novel therapeutics. For instance, Wu et al. have suggested that since the XRCC4 gene is "critical in NHEJ" and is "positively associated with cancer susceptibility", some XRCC4 SNPs such as G-1394T (rs6869366) "may serve as a common SNP for detecting and predict[ing] various cancers (so far for breast, gastric and prostate cancers... )"; and, although further investigation is needed, "they may serve as candidate targets for personalized anticancer drugs".[25] The possibility of detecting endometriosis on this basis has also been mentioned, and this may also possibly lead to the eventual development of treatments.[25][29] In evaluating further possibilities for anticancer treatments, Wu et al. also commented on the importance of “co-treatments of DNA-damaging agents and radiation”.[25] Specifically, Wu et al. noted that the “balance between DNA damage and capacity of DNA repair mechanisms determines the final therapeutic outcome” and “the capacity of cancer cells to complete DNA repair mechanisms is important for therapeutic resistance and has a negative impact upon therapeutic efficacy”, and thus theorized that “[p]harmacological inhibition of recently detected targets of DNA repair with several small-molecule compounds... has the potential to enhance the cytotoxicity of anticancer agents”.[25]
Microcephalic primordial dwarfism
In humans, mutations in the XRCC4 gene cause microcephalic primordial dwarfism, a phenotype characterized by marked microcephaly, facial dysmorphism, developmental delay and short stature.[31] Although immunoglobulin junctional diversity is impaired, these individuals do not show a recognizable immunological phenotype.[31][32] In contrast to individuals with a LIG4 mutation, pancytopenia resulting in bone marrow failure is not observed in individuals with XRCC4 deficiency.[32] At the cellular level, disruption of XRCC4 induces hypersensitivity to agents that induce double-strand breaks, defective double-strand break repair and increased apoptosis after induction of DNA damage.[31]
Anti-XRCC4 antibodies
Anti-XRCC4 antibodies including phosphospecific antibodies to pS260 and pS318 in XRCC4 have been developed.[33][34] Antibodies to XRCC4 can have a variety of uses, including use in immunoassays to conduct research in areas such as DNA damage and repair, non-homologous end joining, transcription factors, epigenetics and nuclear signaling.[34][35]
History
Research carried out in the 1980s revealed that a Chinese hamster ovary (CHO) cell mutant called XR-1 was "extremely sensitive" with regard to being killed by gamma rays during the G1 portion of the cell cycle but, in the same research studies, showed "nearly normal resistance" to gamma-ray damage during the late S phase;[36] and in the course of this research, XR-1's cell-cycle sensitivity was correlated with its inability to repair DNA double-strand breaks produced by ionizing radiation and restriction enzymes.[36][37][38] In particular, in a study using somatic cell hybrids of XR-1 cells and human fibroblasts, Giaccia et al. (1989) showed that the XR-1 mutation was a recessive mutation;[38] and in follow-up to this work, Giaccia et al. (1990) carried out further studies examining the XR-1 mutation (again using somatic cell hybrids formed between XR-1 and human fibroblasts) and were able to map the human complementing gene to chromosome 5 using chromosome-segregation analysis.[39] Giaccia et al, tentatively assigned this human gene the name “XRCC4” (an abbreviation of “X-ray-complementing Chinese hamster gene 4”) and determined that (a) the newly named XRCC4 gene biochemically restored the hamster defect to normal levels of resistance to gamma-ray radiation and bleomycin and (b) the XRCC4 gene restored the proficiency to repair DNA DSBs.[39] Based on these findings, Giaccia et al. proposed that XRCC4 ― as a single gene― was responsible for the XR-1 phenotype.[39]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000152422 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021615 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 11029705.
- ^ PMID 23345432.
- ^ PMID 16478998.
- ^ ISBN 978-0-8053-9592-1.
- ^ PMID 22287571.
- PMID 23321468.
- ^ PMID 15123782.
- ^ PMID 18087292.
- ^ PMID 23012265.
- ^ "Entrez Gene: XRCC4 X-ray repair complementing defective repair in Chinese hamster cells 4".
- PMID 11080143.
- PMID 17124166.
- ^ PMID 19332554.
- ISBN 978-1-4292-3413-9.
- PMID 19514464.
- ^ S2CID 15164549.
- ^ PMID 22994773.
- S2CID 45344195.
- S2CID 43551117.
- ^ PMID 19064702.
- ^ PMID 18991789.
- PMID 27391797.
- PMID 12218164.
- S2CID 21179835.
- ^ S2CID 11018.
- PMID 22237628.
- ^ PMID 25839420.
- ^ PMID 25728776.
- PMID 22228831.
- ^ a b "Anti-XRCC4 antibody - ChIP Grade (ab145) | Abcam". Abcam.; "XRCC4 antibody | Western | SAB2102728". Sigma-Aldrich.
- S2CID 24883245.
- ^ S2CID 31533353.
- PMID 3406371.
- ^ S2CID 21199573.
- ^ PMID 1697445.
Further reading
- Lieber MR (1999). "The biochemistry and biological significance of nonhomologous DNA end joining: an essential repair process in multicellular eukaryotes". Genes Cells. 4 (2): 77–85. S2CID 28371481.
- Li Z, Otevrel T, Gao Y, Cheng HL, Seed B, Stamato TD, Taccioli GE, Alt FW (1996). "The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination". Cell. 83 (7): 1079–89. PMID 8548796.
- Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, Lieber MR (1997). "Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells". Nature. 388 (6641): 492–5. S2CID 4349909.
- Critchlow SE, Bowater RP, Jackson SP (1997). "Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV". Curr. Biol. 7 (8): 588–98. PMID 9259561.
- Mizuta R, Cheng HL, Gao Y, Alt FW (1998). "Molecular genetic characterization of XRCC4 function". Int. Immunol. 9 (10): 1607–13. PMID 9352367.
- Leber R, Wise TW, Mizuta R, Meek K (1998). "The XRCC4 gene product is a target for and interacts with the DNA-dependent protein kinase". J. Biol. Chem. 273 (3): 1794–801. PMID 9430729.
- Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ, Sekiguchi JM, Rathbun GA, Swat W, Wang J, Bronson RT, Malynn BA, Bryans M, Zhu C, Chaudhuri J, Davidson L, Ferrini R, Stamato T, Orkin SH, Greenberg ME, Alt FW (1999). "A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis". Cell. 95 (7): 891–902. PMID 9875844.
- Modesti M, Hesse JE, Gellert M (1999). "DNA binding of Xrcc4 protein is associated with V(D)J recombination but not with stimulation of DNA ligase IV activity". EMBO J. 18 (7): 2008–18. PMID 10202163.
- Nick McElhinny SA, Snowden CM, McCarville J, Ramsden DA (2000). "Ku recruits the XRCC4-ligase IV complex to DNA ends". Mol. Cell. Biol. 20 (9): 2996–3003. PMID 10757784.
- Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM, Chaudhuri J, Horner J, DePinho RA, Alt FW (2000). "Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development". Nature. 404 (6780): 897–900. S2CID 4321552.
- Chen L, Trujillo K, Sung P, Tomkinson AE (2000). "Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase". J. Biol. Chem. 275 (34): 26196–205. PMID 10854421.
- Lee KJ, Huang J, Takeda Y, Dynan WS (2000). "DNA ligase IV and XRCC4 form a stable mixed tetramer that functions synergistically with other repair factors in a cell-free end-joining system". J. Biol. Chem. 275 (44): 34787–96. PMID 10945980.
- Ford BN, Ruttan CC, Kyle VL, Brackley ME, Glickman BW (2000). "Identification of single nucleotide polymorphisms in human DNA repair genes". Carcinogenesis. 21 (11): 1977–81. PMID 11062157.
- Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L (2002). "Crystal structure of an Xrcc4-DNA ligase IV complex". Nat. Struct. Biol. 8 (12): 1015–9. S2CID 21218268.
- Lee KJ, Dong X, Wang J, Takeda Y, Dynan WS (2002). "Identification of human autoantibodies to the DNA ligase IV/XRCC4 complex and mapping of an autoimmune epitope to a potential regulatory region". J. Immunol. 169 (6): 3413–21. PMID 12218164.
- Hsu HL, Yannone SM, Chen DJ (2003). "Defining interactions between DNA-PK and ligase IV/XRCC4". DNA Repair (Amst.). 1 (3): 225–35. S2CID 29007955.
External links
- XRCC4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook XRCC4
- Overview of all the structural information available in the PDB for UniProt: Q13426 (DNA repair protein XRCC4) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.