X-ray Repair Cross-complementing Protein Research Articles

Dynamic light scattering study of base excision DNA repair proteins and their complexes

Base excision repair (BER) involves many enzymes acting in a coordinated fashion at the most common types of DNA damage. The coordination is facilitated by interactions between the enzymes and accessory proteins, X-ray repair cross-complementing protein 1 (XRCC1) and poly(ADP-ribose) polymerase 1 (PARP1). Here we use dynamic light scattering (DLS) technique to determine the hydrodynamic sizes of several BER enzymes and proteins, DNA polymerase β (Polβ), apurinic/apyrimidinic endonuclease 1 (APE1), tyrosyl-DNA phosphodiesterase 1 (TDP1), XRCC1 and PARP1, present alone or in the equimolar mixtures with each other. From the DLS data combined with glutaraldehyde cross-linking experiments and previous quantitative binding data the oligomeric states of BER proteins and their complexes are estimated. All the proteins have been proposed to form homodimers upon their self-association. The most probable oligomerization state of the binary complexes formed by PARP1 with various proteins is a heterotetramer. The oligomerization state of the binary complexes formed by XRCC1 varies from heterodimer to heterotetramer, depending on the partner. The DLS technique is applied for the first time to measure the hydrodynamic sizes of PARP1 molecules covalently bound with poly(ADP-ribose) (PAR) synthesized upon the automodification reaction. PARP1 has been detected to form huge conglomerates stabilized by Mg2+ coordinated bonds with PAR polymers.

PML-like subnuclear bodies, containing XRCC1, juxtaposed to DNA replication-based single-strand breaks.

DNA lesions induce recruitment and accumulation of various repair factors, resulting in formation of discrete nuclear foci. Using superresolution fluorescence microscopy as well as live cell and quantitative imaging, we demonstrate that X-ray repair cross-complementing protein 1 (XRCC1), a key factor in single-strand break and base excision repair, is recruited into nuclear bodies formed in response to replication-related single-strand breaks. Intriguingly, these bodies are assembled immediately in the vicinity of these breaks and never fully colocalize with replication foci. They are structurally organized, containing canonical promyelocytic leukemia (PML) nuclear body protein SP100 concentrated in a peripheral layer, and XRCC1 in the center. They also contain other factors, including PML, poly(ADP-ribose) polymerase 1 (PARP1), ligase IIIα, and origin recognition complex subunit 5. The breast cancer 1 and -2 C terminus domains of XRCC1 are essential for formation of these repair foci. These results reveal that XRCC1-contaning foci constitute newly recognized PML-like nuclear bodies that accrete and locally deliver essential factors for repair of single-strand DNA breaks in replication regions.-Kordon, M. M., Szczurek, A., Berniak, K., Szelest, O., Solarczyk, K., Tworzydło, M., Wachsmann-Hogiu, S., Vaahtokari, A., Cremer, C., Pederson, T., Dobrucki, J. W. PML-like subnuclear bodies, containing XRCC1, juxtaposed to DNA replication-based single-strand breaks.

Interaction Between Environmental Risk Factors and Catechol-O-Methyltransferase (COMT) and X-Ray Repair Cross-Complementing Protein 1 (XRCC1) Gene Polymorphisms in Risk of Lung Cancer Among Non-Smoking Chinese Women: A Case-Control Study.

BackgrpoundVarious studies have highlighted the link between polymorphisms in the XRCC1 gene (encoding X-ray repair cross-complementing group 1) with the incidence of decreased DNA repair capacity and an increased predisposition to cancer. Catechol-O-methyltransferase (COMT) plays a crucial role in estrogen-induced cancers. In the present study was analyzed the potential influence of XRCC1 and COMT gene polymorphisms as predisposing factors from a lung cancer perspective, in addition to conducting an investigation into their interaction with environmental risk factors in relation to lung cancer among non-smoking Chinese women.Material/MethodsThe XRCC1 gene T-77C, Arg194Trp, Arg280His, Arg399Gln, COMT gene 186C>T, and Val158Met mutations were evaluated in peripheral blood collected from 261 non-smoking female patients diagnosed with primary lung cancer and 265 female patients with benign lung disease.ResultThe results obtained from this study demonstrated that XRCC1–77TC + CC, XRCC1 399Gln/Gln, COMT 186CT + TT, COMT 158Val/Met genotypes, type of occupation, cooking-oil fumes, and soot exposures were all independent risk factors involved with the occurrence of lung cancer among non-smoking women. Moreover, interactions between environmental exposure factors as well as XRCC1 and COMT gene polymorphisms were determined to play significant contributory roles regarding susceptibility of non-smoking females to lung cancer.ConclusionsTaken together, T-77C and Arg399Gln polymorphisms of the XRCC1 gene, as well as the 186C>T and Val158Met polymorphisms of the COMT gene, increased the risk of lung cancer in non-smoking women, with the factors of occupation type, cooking-oil fumes, and soot exposures representing key contributing factors.

Association between XRCC1 single-nucleotide polymorphisms and susceptibility to nasopharyngeal carcinoma: An update meta-analysis.

Many studies have investigated polymorphisms of X-ray repair cross-complementing protein 1 (XRCC1) and risk of nasopharyngeal carcinoma (NPC), but the results are somewhat contradictory in different studies. There is an urgent need to keep in step with the relevant observational studies to more comprehend the effects of XRCC1 variants on the NPC risk. A systematic literature search accompanied with meta-analysis was carried out to obtain a detailed evaluation on the association between XRCC1 polymorphisms and NPC risk. Meta-analyses showed that there was no statistically significant association observed between Arg194Trp/Arg280His variants in the XRCC1 gene and NPC risk with all genetic models, when relatively larger samples were pooled into the update meta-analysis. The reassessment suggested NPC risk was significantly increased with Arg399Gln polymorphism. The significant association was identified in homozygous, recessive, and allelic models, more than previously reported. We confirmed that Arg399Gln polymorphism of XRCC1 gene is a potential predictor for susceptibility to NPC, especially for Asians. More studies are required to evaluate the association in different populations.

The transcription-coupled DNA repair-initiating protein CSB promotes XRCC1 recruitment to oxidative DNA damage.

Transcription-coupled nucleotide excision repair factor Cockayne syndrome protein B (CSB) was suggested to function in the repair of oxidative DNA damage. However thus far, no clear role for CSB in base excision repair (BER), the dedicated pathway to remove abundant oxidative DNA damage, could be established. Using live cell imaging with a laser-assisted procedure to locally induce 8-oxo-7,8-dihydroguanine (8-oxoG) lesions, we previously showed that CSB is recruited to these lesions in a transcription-dependent but NER-independent fashion. Here we showed that recruitment of the preferred 8-oxoG-glycosylase 1 (OGG1) is independent of CSB or active transcription. In contrast, recruitment of the BER-scaffolding protein, X-ray repair cross-complementing protein 1 (XRCC1), to 8-oxoG lesions is stimulated by CSB and transcription. Remarkably, recruitment of XRCC1 to BER-unrelated single strand breaks (SSBs) does not require CSB or transcription. Together, our results suggest a specific transcription-dependent role for CSB in recruiting XRCC1 to BER-generated SSBs, whereas XRCC1 recruitment to SSBs generated independently of BER relies predominantly on PARP activation. Based on our results, we propose a model in which CSB plays a role in facilitating BER progression at transcribed genes, probably to allow XRCC1 recruitment to BER-intermediates masked by RNA polymerase II complexes stalled at these intermediates.

Role of PON1, SOD2, OGG1, XRCC1, and XRCC4 polymorphisms on modulation of DNA damage in workers occupationally exposed to pesticides

Tobacco farming has been proving to induce poor health outcomes in agricultural workers, genomic instability being the triggering one. This study evaluated influence of PON1 (paraoxonase 1), SOD2 (superoxide dismutase), OGG1 (8-oxoguanine glycosylase), XRCC1 (X-ray repair cross-complementing protein 1), and XRCC4 (X-ray repair cross-complementing protein 4) genes polymorphisms on DNA damage in 121 subjects occupationally exposed to pesticides mixtures and nicotine at tobacco fields and 121 non-exposed individuals. Inorganic elements (Cl, P, S and Zn) and cotinine levels were found increased in farmers, confirming exposure. Results show higher frequencies of buccal micronucleus (MN), nuclear buds (NBUD), binucleated cells (BN) and damage index (comet assay), reduced telomere length (TL), and increased parameters of oxidative stress in farmers compared to non-exposed individuals. PON1 Gln/Gln genotype was associated with increased MN frequency. SOD2 Val/Val showed association with increased frequency of MN and NBUD and decreased antioxidant activity. The XRCC1 Arg/Arg showed protective effect for MN, BN and TL, which was also positively influenced by OGG1 -/Cys. MN was decreased in XRCC4 -/Ile farmers. These genotypes also showed a risk for antioxidant activity. Our study proposes that PON1 and SOD2 variants play a role in xenobiotic-metabolizing system in farmers, while base excision repair (BER) pathway could be the repair mechanism involved in genomic instability suffered by tobacco farmers.

XRCC3 polymorphism is associated with hypertension-induced left ventricular hypertrophy.

Deficiency of X-ray repair cross-complementing protein 3 (XRCC3), a DNA-damage repair molecule, and the 241Met variant of XRCC3 have been reported to increase endoreduplication, which induces polyploidy. The aims of this study were to determine the impact of the XRCC3 polymorphism on the incidence of hypertension-induced left ventricular hypertrophy (LVH) and to investigate the mechanisms underlying any potential relationship. Patients undergoing chronic hemodialysis (n = 77) were genotyped to assess for the XRCC3 Thr241Met polymorphism. The XRCC3 241Thr/Met genotype was more frequent in the LVH (+) group than in the LVH (-) group (42.3 vs. 13.7%, χ2 = 7.85, p = 0.0051). To investigate possible mechanisms underlying these observations, human XRCC3 cDNA of 241Thr or that of 241Met was introduced into cultured CHO cells. The surface area of CHO cells expressing XRCC3 241Met was larger than that expressing 241Thr. Spontaneous DNA double-strand breaks accumulated to a greater degree in NIH3T3 cells expressing 241Met (3T3-241Met) than in those expressing 241Thr (3T3-241Thr). DNA damage caused by radiationinduced cell senescence more frequently in 3T3-241Met. The levels of basal and TNF-α-stimulated MCP-1 mRNA and protein secretion were higher in 3T3-241Met. Finally, FACS analysis revealed that the cell percentage in G2/M phase including polyploidy was significantly higher in 3T3-241Met than in 3T3-241Thr. Furthermore, the basal level of MCP-1 mRNA positively correlated with the cell percentage in G2/M phase and polyploidy. These data suggest that the XRCC3 241Met increases the risk of LVH via accumulation of DNA damage, thereby altering cell cycle progression and inducing cell senescence and a proinflammatory phenotype.

Predictive value of ERCC1, ERCC2, and XRCC expression for patients with locally advanced or metastatic gastric cancer treated with neoadjuvant FOLFOX chemotherapy

Background: The dismal outcome in patients with locally advanced or metastatic gastric cancer highlights the need for effective systemic neoadjuvant chemotherapy to improve clinical results. This study evaluated the correlation between the expression of three DNA repair genes, namely the excision repair cross-complementing group 1 (ERCC1), excision repair cross-complementing group 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1), and the clinical outcome of patients with locally advanced or metastatic gastric cancer treated with FOLFOX-4 neoadjuvant chemotherapy.

Association of Polymorphisms in DNA Repair Gene XRCC3 with Asthma in Taiwan.

Accumulating evidence suggests that DNA damage and repair play a role in asthma etiology, however, little is known about the contribution of genotypes of DNA repair genes to asthma susceptibility. This study aimed to examine the contribution of genotypes of DNA double-strand break repair gene X-ray repair cross complementing protein 3 (XRCC3) and its polymorphisms to asthma risk in the Taiwanese. Associations of seven XRCC3 genotypes, namely rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539 and rs28903081, with the risk of asthma were investigated among 198 patients with asthma and 453 non-asthma controls by polymerase chain reaction-restriction fragment length polymorphism genotyping methodology. Unlike Caucasian populations, no polymorphic genotypes at XRCC3 rs3212057 or rs28903081 were found among the Taiwanese. For the genotypes of XRCC3 rs1799794, rs45603942, rs861530, rs1799796 and rs861539, the percentages of hetero-and homo-variant genotypes were not differentially represented between the asthma patient and the non-asthma control groups. In addition, there was no differential distribution of allelic frequencies for these XRCC3 polymorphic sites between the two groups. No interaction of these genotypes with gender or age were found. Although XRCC3 plays a role in asthma etiology, the variant XRCC3 genotypes do not serve as practicable predictive markers for asthma risk in Taiwanese.

Cell micro-irradiation with MeV protons counted by an ultra-thin diamond membrane

We report the development of thin single crystal diamond membranes suitable for dose control in targeted cell irradiation experiments with a proton microbeam. A specific design was achieved to deliver single protons with a hit detection efficiency approaching 100%. The membranes have thicknesses between 1.8 and 3 μm and are used as vacuum windows on the microbeam line. The impact of these transmission detectors on the microbeam spot size is estimated by Monte-Carlo simulations, indicating that a beam lateral resolution below 2 μm is achieved. This is confirmed by experiments showing the accumulation online of X-ray Repair Cross-Complementing protein 1 (XRCC1)-Green Fluorescent Protein (GFP) at DNA damaged sites in living cells.

Polymorphism of genes encoding proteins of DNA repair vs. occupational and environmental exposure to lead, arsenic and pesticides

Genetic polymorphism is associated with the occurrence of at least 2 different alleles in the locus with a frequency higher than 1% in the population. Among polymorphisms we can find single nucleotide polymorphism (SNP) and polymorphism of variable number of tandem repeats. The presence of certain polymorphisms in genes encoding DNA repair enzymes is associated with the speed and efficiency of DNA repair and can protect or expose humans to the effects provoked by xenobiotics. Chemicals, such as lead, arsenic pesticides are considered to exhibit strong toxicity. There are many different polymorphisms in genes encoding DNA repair enzymes, which determine the speed and efficiency of DNA damage repair induced by these xenobiotics. In the case of lead, the influence of various polymorphisms, such as APE1 (apurinic/apyrimidinic endonuclease 1) (rs1130409), hOGG1 (human 8-oxoguanine glycosylase) (rs1052133), XRCC1 (X-ray repair cross-complementing protein group 1) (rs25487), XRCC1 (rs1799782) and XRCC3 (X-ray repair cross-complementing protein group 3) (rs861539) were described. For arsenic polymorphisms, such as ERCC2 (excision repair cross-complementing) (rs13181), XRCC3 (rs861539), APE1 (rs1130409) and hOGG1 (rs1052133) were examined. As to pesticides, separate and combined effects of polymorphisms in genes encoding DNA repair enzymes, such as XRCC1 (rs1799782), hOGG1 (rs1052133), XRCC4 (X-ray repair cross-complementing protein group 4) (rs28360135) and the gene encoding the detoxification enzyme PON1 paraoxonase (rs662) were reported. Med Pr 2018;69(2):225-235.

Sunitinib Inhibits Breast Cancer Cell Proliferation by Inducing Apoptosis, Cell-cycle Arrest and DNA Repair While Inhibiting NF-κB Signaling Pathways.

The tyrosine kinase inhibitor sunitinib was recently approved for use against gastrointestinal stromal tumors and advanced renal cell carcinoma. Yet, the protective effect of sunitinib against breast cancer has been poorly investigated. In this study, we investigated the antiproliferative and apoptogenic effects of sunitinib and the possible mechanism involved against the MCF7 human breast cancer cell line. Treatment of MCF7 cells with sunitinib caused concentration-dependent cell growth suppression due to apoptosis. Apoptotic death induced by sunitinib in MCF7 cells was mediated by activation of caspase-3 and p53 mRNA and protein expression and an increase in the percentage of apoptotic cells (40%) as determined by flow cytometry. Apoptosis was associated with a significant inhibition of nuclear factor-kappa B mRNA and protein expression. Mechanistically, blocking of de novo RNA synthesis by actinomycin D significantly inhibited sunitinib-induced expression of p53 mRNA, but not that of caspase-3, indicating involvement of a transcriptional mechanism. This apoptosis-mediated inhibition of MCF7 cell growth was attributed to inhibition of cell cycle-related genes (cyclin D1 and cyclin E2) and arrest of MCF7 cells in the G2/M phase in the cell cycle, allowing up-regulation of expression of DNA repair genes such as x-ray repair cross-complementing protein 1. In addition, sunitinib exhibited concentration-dependent induction of oxidative stress genes (heme oxygenase 1 and glutathione transferase A1) through the nuclear factor erythroid 2-related factor 2 pathway. These findings lead us to propose that sunitinib suppressed the proliferation of MCF7 cells via cell-cycle arrest and apoptotic- and oxidative stress-mediated pathways.

Triptolide induces DNA breaks, activates caspase-3-dependent apoptosis and sensitizes B-cell lymphoma to poly(ADP-ribose) polymerase 1 and phosphoinositide 3-kinase inhibitors.

Triptolide is the primary compound isolated from Tripterygium wilfordii, which has been reported to inhibit nucleotide excision repair as well as exhibit anti-inflammatory and antitumor activities. However, the action of triptolide in DNA breaks remains unknown. The present study investigated the effects of triptolide in the induction of DNA breaks and apoptosis in a murine B-cell lymphoma cell line, CH12F3. An MTT assay revealed that X-ray repair cross-complementing protein 1 (XRCC1)-/- CH12F3 cells were more sensitive to 6 nM triptolide compared with the wild-type CH12F3 cells, which suggests that low levels of triptolide induce DNA breaks in a manner that is dependent on the XRCC1-mediated repair pathway. Flow cytometric analysis identified that 50 nM triptolide increased the phospho-histone H2AX level, demonstrating that triptolide induces double-strand breaks. Western blot analysis revealed that triptolide up-regulated Rad51 and nuclear proliferating cell nuclear antigen. Annexin V/propidium iodide staining identified that triptolide promoted apoptosis and western blot analysis confirmed that triptolide activated caspase-3-dependent apoptosis. The results of the present study also demonstrated that 5 nM triptolide sensitized CH12F3 lymphoma cells to poly(ADP-ribose) polymerase 1 and phosphoinositide 3-kinase inhibitors, suggesting that triptolide may be a potent antitumor drug for sensitizing lymphoma cells to chemotherapeutic agents.

CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair pathways and selectively inhibits ATM-deficient cell growth in vitro.

CC-115, a selective dual inhibitor of the mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase (DNA-PK), is undergoing Phase 1 clinical studies. Here we report the characterization of DNA-PK inhibitory activity of CC-115 in cancer cell lines. CC-115 inhibits auto-phosphorylation of the catalytic subunit of DNA-PK (DNA-PKcs) at the S2056 site (pDNA-PK S2056), leading to blockade of DNA-PK-mediated non-homologous end joining (NHEJ). CC-115 also indirectly reduces the phosphorylation of ataxia-telangiectasia mutated kinase (ATM) at S1981 and its substrates as well as homologous recombination (HR). The mTOR kinase and DNA-PK inhibitory activity of CC-115 leads to not only potent anti-tumor activity against a large panel of hematopoietic and solid cancer cell lines but also strong induction of apoptosis in a subset of cancer lines. Mechanistically, CC-115 prevents NHEJ by inhibiting the dissociation of DNA-PKcs, X-ray repair cross-complementing protein 4 (XRCC4), and DNA ligase IV from DNA ends. CC-115 inhibits colony formation of ATM-deficient cells more potently than ATM-proficient cells, indicating that inhibition of DNA-PK is synthetically lethal with the loss of functional ATM. In conclusion, CC-115 inhibits both mTOR signaling and NHEJ and HR by direct inhibition of DNA-PK. The mechanistic data not only provide selection of potential pharmacodynamic (PD) markers but also support CC-115 clinical development in patients with ATM-deficient tumors.

XRCC1 Arg399Gln gene polymorphism and hepatocellular carcinoma risk in the Italian population.

The human X-ray repair cross-complementing protein 1 (XRCC1) gene encodes for one of the major repair factors involved in base excision repair (BER), which is reported to be associated with the risk of several cancers. A few studies have explored the association between risk of hepatocellular carcinoma (HCC) and single-nucleotide polymorphisms (SNPs) in different DNA repair genes, with contradictory results. The purpose of this study was to evaluate the association between XRCC1 Arg399Gln polymorphism and susceptibility to HCC. A total of 89 HCC patients and 99 randomly selected healthy controls were enrolled. Genotyping of XRCC1 rs25487 was performed by high-resolution melting analysis and Sanger sequencing. On univariate analysis, a statistically significant association was found between risk of HCC and XRCC1 399Arg/Gln genotype (odd ratio [OR] = 1.88; 95% CI, 1.04-3.43), which was confirmed after adjusting by sex (OR = 1.94; 95% CI, 1.04-3.63). Although not significant, Kaplan-Meier analysis showed a decreased median survival in Arg/Gln genotype carriers in comparison with Arg/Arg carriers. To our knowledge, this is the first study reporting an association between BER SNP and HCC risk in a population of central-southern Italy.

The Human Ligase IIIα-XRCC1 Protein Complex Performs DNA Nick Repair after Transient Unwrapping of Nucleosomal DNA

Reactive oxygen species generate potentially cytotoxic and mutagenic lesions in DNA, both between and within the nucleosomes that package DNA in chromatin. The vast majority of these lesions are subject to base excision repair (BER). Enzymes that catalyze the first three steps in BER can act at many sites in nucleosomes without the aid of chromatin-remodeling agents and without irreversibly disrupting the host nucleosome. Here we show that the same is true for a protein complex comprising DNA ligase IIIα and the scaffolding protein X-ray repair cross-complementing protein 1 (XRCC1), which completes the fourth and final step in (short-patch) BER. Using in vitro assembled nucleosomes containing discretely positioned DNA nicks, our evidence indicates that the ligase IIIα-XRCC1 complex binds to DNA nicks in nucleosomes only when they are exposed by periodic, spontaneous partial unwrapping of DNA from the histone octamer; that the scaffolding protein XRCC1 enhances the ligation; that the ligation occurs within a complex that ligase IIIα-XRCC1 forms with the host nucleosome; and that the ligase IIIα-XRCC1-nucleosome complex decays when ligation is complete, allowing the host nucleosome to return to its native configuration. Taken together, our results illustrate ways in which dynamic properties intrinsic to nucleosomes may contribute to the discovery and efficient repair of base damage in chromatin.

Different DNA End Configurations Dictate Which NHEJ Components Are Most Important for Joining Efficiency

The nonhomologous DNA end-joining (NHEJ) pathway is a key mechanism for repairing dsDNA breaks that occur often in eukaryotic cells. In the simplest model, these breaks are first recognized by Ku, which then interacts with other NHEJ proteins to improve their affinity at DNA ends. These include DNA-PKcs and Artemis for trimming the DNA ends; DNA polymerase μ and λ to add nucleotides; and the DNA ligase IV complex to ligate the ends with the additional factors, XRCC4 (X-ray repair cross-complementing protein 4), XLF (XRCC4-like factor/Cernunos), and PAXX (paralog of XRCC4 and XLF). In vivo studies have demonstrated the degrees of importance of these NHEJ proteins in the mechanism of repair of dsDNA breaks, but interpretations can be confounded by other cellular processes. In vitro studies with NHEJ proteins have been performed to evaluate the nucleolytic resection, polymerization, and ligation steps, but a complete system has been elusive. Here we have developed a NHEJ reconstitution system that includes the nuclease, polymerase, and ligase components to evaluate relative NHEJ efficiency and analyze ligated junctional sequences for various types of DNA ends, including blunt, 5′ overhangs, and 3′ overhangs. We find that different dsDNA end structures have differential dependence on these enzymatic components. The dependence of some end joining on only Ku and XRCC4·DNA ligase IV allows us to formulate a physical model that incorporates nuclease and polymerase components as needed.

The Relationship Between XRCC1 Arg399Gln Polymorphism, Alcohol Consumption and Colorectal Cancer: One of the Alcohol Forbidding Reasons in Islam

Cancers start when cells in the body begin uncontrolled growth. Cancers are one of the major reasons of morbidity and death universally, and can spread to other organs of the body. colorectal cancer (CRC) is a type of cancer that starts in the colon or rectum. It has the third rank in occurrence of cancer and mortality in the US (1, 2). It is a very serious and dangerous problem worldwide (3). On the other hand, X-Ray repair cross-complementing protein 1 (XRCC1) plays an important role in the repair of DNA damage, and this repair implementation is via base lesions excision repair (BER) pathway (4). Free radical intermediates may generate DNA base lesions that should be removed via the BER. It should be noted that the reduced repair capacity due to XRCC1 polymorphisms is a venturesome factor for body’s health; Lunn et al. showed that the XRCC1 Arg399Gln polymorphism could cause defective DNA repair (5, 6). XRCC1 Arg399Gln polymorphism can result in lung cancer, leukemia, lymphoma, breast cancer and hepatocellular carcinoma (7-10). Our goal was to detect the relationship between XRCC1 Arg399Gln polymorphism and CRC and also to determine the efficacy of alcohol consumption on this relationship. Regarding the relationship between XRCC1 Arg399Gln polymorphism and CRC, some studies have shown that XRCC1 Arg399Gln polymorphism could cause CRC occurrence (11, 12). In Wu’s study, it was suggested that this polymorphism has a potential to increase CRC susceptibility (13). Similarly, Chang-Jiang Qin et al. detected the association between the polymorphism of XRCC1 Arg399Gln and CRC (14). Also two meta-analyses confirmed that XRCC1 Arg399Gln polymorphism is a predisposing factor for the development of CRC (15, 16). On the other hand, researchers also evaluated the interaction between three polymorphic sites of XRCC1 gene and drinking habit; the idea was based on the role of reactive oxygen species as relevant genotoxins that might account for the effects of alcohol; and they indicated a higher risk in people with Arg399Gln allele and alcohol drinking. Also, they suggested that chronic alcohol consumption could reduce XRCC1 protein activity (13). In addition, scholars found that the effect of high alcohol intake that increased the risk of CRC was more remarkable in carriers of the XRCC1 codons 194 Trp allele or 399 Gln allele (17-19), and as mentioned above, XRCC1 polymorphisms are repair capacity reducers, so in alcoholism, XRCC1 can’t become involved in the BER of alcohol-induced DNA damage. In conclusion, CRC is seriously and significantly associated with XRCC1 Arg399Gln polymorphism. The findings demonstrate that alcoholic drinks possess adverse effects on the colon and rectum because these drinks are associated with problems linked to XRCC1 Arg399Gln polymorphism in creation and development of CRC. Also, it should be noted that according to the Holy Quran, consumption of anything that causes drunkenness is forbidden such as alcoholic drinks (20). Finally, alcoholic drinks are hazardous factors in relation to CRC and this is one of the detected alcohol forbidding reasons in Islam. So via adherence to preachments of Islam about lack of alcohol consumption, one can promote their social and personal health.

Influence of XRCC4 expression in esophageal cancer cellson the response to radiotherapy.

DNA double-strand break (DSB) is one of the most serious forms of damage induced by ionizing irradiation and is mainly repaired by the non-homologous end joining (NHEJ) repair. Immunohistochemical analysis of proteins involved in NHEJ, such as XRCC4 (X-ray repair cross-complementing protein 4), Ku86 and DNA-PKcs (DNA-dependent protein kinase, catalytic subunits), may be useful for predicting tumor radiosensitivity. We examined 92 patients with esophageal squamous cell carcinoma (ECSS) who were treated by radiotherapy between 1999 and 2008. Immunohistochemical examination of tumor tissue for Ki-67 and DSB-related proteins, including XRCC4, Ku86, and DNA-PKcs, was performed using pretreatment biopsy specimens. Low expression of XRCC4 was detected in 31 of 92 examined samples (33.7%). The 5-year overall survival (OS) rate was 67.7% in the low expression group and 31.0% in the high expression group (P=0.00). Multivariate analysis confirmed that advanced T-stage (HR 3.24, P=0.01), radiation dose less than 66Gy (HR 2.23, P=0.02), absence of systemic chemotherapy (HR 2.59, P=0.05), and high expression of XRCC4 (HR 12.0, P=0.02) were independent prognostic factors for predicting poor OS. Other DSB-related proteins and Ki-67 were not predictive factors. XRCC4 expression might have an influence on results of radiotherapy for patients with ESCC.

Mutations in XRCC4 cause primordial dwarfism without causing immunodeficiency.

In successive reports from 2014 to 2015, X-ray repair cross-complementing protein 4 (XRCC4) has been identified as a novel causative gene of primordial dwarfism. XRCC4 is indispensable for non-homologous end joining (NHEJ), the major pathway for repairing DNA double-strand breaks. As NHEJ is essential for V(D)J recombination during lymphocyte development, it is generally believed that abnormalities in XRCC4 cause severe combined immunodeficiency. Contrary to expectations, however, no overt immunodeficiency has been observed in patients with primordial dwarfism harboring XRCC4 mutations. Here, we describe the various XRCC4 mutations that lead to disease and discuss their impact on NHEJ and V(D)J recombination.