Electroacupuncture at the Renzhong (DU 26) and Neiguan (PC 6) acupoints repairs the DNA of nervous tissue supplied by the middle cerebral artery in rats

This study compares the changes of DNA repair in brain tissue dominated by the middle cerebral artery after electroacupuncture at the acupoints of Renzhong （DU 26）, Neiguan （PC 6）, Quchi （LI 11） and Zusanli （ST 36） in rats. In the apurinic/apyrimidinic endonuclease DNA basic group reparative excision experiments, the apurinic/apyrimidinic endonuclease activity of brain tissue increased slightly after electroacupuncture in rats. In the DNA polymerase β （Pol β）experiments, the Pol β ac-tivity of brain tissue increased after electroacupuncture, especially at DU 26 and PC 6. In the DNA ligase experiments, the expression of DNA ligase 1 in brain tissue increased significantly after electroacupuncture. These findings demonstrate increased activity of apurinic/apyrimidinic en-donuclease, Pol β and DNA ligase 1 after electroacupuncture at DU 26 and PC 6. Also, DNA repair in brain tissue supplied by the middle cerebral artery is promoted after electroacupuncture at DU 26 and PC 6, which are more effective than the LI 11 and ST 36 acupoints .

The DNA damage repair complex MoMMS21-MoSMC5 is required for infection-related development and pathogenicity of Magnaporthe oryzae

The conserved DNA damage repair complex,MMS21-SMC5/6(Methyl methane sulfonate 21-Structural maintenance of chromosomes 5/6),has been extensively studied in yeast,animals,and plants.However,its role in phytopathogenic fungi,particularly in the highly destructive rice blast fungus Magnaporthe oryzae,remains unknown.In this study,we functionally characterized the homologues of this complex,MoMMS21 and MoSMC5,in M.oryzae.We first demonstrated the importance of DNA damage repair in M.oryzae by showing that the DNA damage inducer phleomycin inhibited vegetative growth,infection-related development and pathogenicity in this fungus.Additionally,we discovered that MoMMS21 and MoSMC5 interacted in the nuclei,suggesting that they also function as a complex in M.oryzae.Gene deletion experiments revealed that both MoMMS21 and MoSMC5 are required for infection-related development and pathogenicity in M.oryzae,while only MoMMS21 deletion affected growth and sensitivity to phleomycin,indicating its specific involvement in DNA damage repair.Overall,our results provide insights into the roles of MoMMS21 and MoSMC5 in M.oryzae,highlighting their functions beyond DNA damage repair.

LncRNA HOTAIR promotes DNA damage repair and radioresistance by targeting ATR in colorectal cancer

Long non-coding RNAs(lncRNAs)have been implicated in cancer progression and drug resistance development.Moreover,there is evidence that lncRNA HOX transcript antisense intergenic RNA(HOTAIR)is involved in colorectal cancer(CRC)progression.The present study aimed to examine the functional role of lncRNA HOTAIR in conferring radiotherapy resistance in CRC cells,as well as the underlying mechanism.The relative expression levels of HOTAIR were examined in 70 pairs of CRC tumor and para-cancerous tissues,as well as in radiosensitive and radioresistant samples.The correlations between HOTAIR expression levels and clinical features of patients with CRC were assessed using the Chi-square test.Functional assays such as cell proliferation,colony formation and apoptosis assays were conducted to determine the radiosensitivity in CRC cells with HOTAIR silencing after treatment with different doses of radiation.RNA pull-down assay andfluorescence in situ hybridization(FISH)were used to determine the interaction between HOTAIR and DNA damage response mediator ataxia-telangiectasia mutated-and Rad3-related(ATR).HOTAIR was significantly upregulated in CRC tumor tissues,especially in radioresistant tumor samples.The elevated expression of HOTAIR was correlated with more advanced histological grades,distance metastasis and the poor prognosis in patients with CRC.Silencing HOTAIR suppressed the proliferation and promoted apoptosis and radiosensitivity in CRC cells.HOTAIR knockdown also inhibited the tumorigenesis of CRC cells and enhanced the sensitivity to radiotherapy in a mouse xenograft model.Moreover,the data showed that HOTAIR could interact with ATR to regulate the DNA damage repair signaling pathway.Silencing HOTAIR impaired the ATR-ATR interacting protein(ATRIP)complex and signaling in cell cycle progression.Collectively,the present results indicate that lncRNA HOTAIR facilitates the DNA damage response pathway and promotes radioresistance in CRC cells by targeting ATR.

In Vivo Improvements in Facial Appearance and in Vitro Changes in Gene Expression Using a Topical Formulation Designed to Repair Environmentally Induced DNA Damage

Background: While sunscreen has been accepted as a mainline defence against photodamage from ultraviolet, visible light and near-infrared radiation, there appears to be a lack of research into photorepair. The concept of protecting the skin during the day and repairing cellular damage at night is intuitive, yet specific strategies revolving around combinations of proven reparative active ingredients remain unelucidated. Purpose: To investigate the efficacy of a solar repair Formulation following ultraviolet and environmental exposure in order to improve overall skin health and appearance through three hypotheses: The Formulation increases expression of DNA repair mechanisms markers;The Formulation enhances overall skin appearance through reducing signs of inflammation, elevating hydration, reinforcing skin firmness and amplifying radiance;In-Vivo efficacy test results are aligned with measured gene expression changes. Methods: The Formulation (#6NIC1.V1.1-1) was tested for: In-vitro LDH cytotoxicity activity, In-vitro qPCR gene expression with and without ultraviolet exposure on a reconstructed 3-dimensional skin model, and In-Vivo efficacy study on a panel of 22 participants objectively and subjectively. Results: Skin radiance, firmness, hydration, redness, and inflammation are significantly improved after In-Vivo skin exposure to the Formulation and environmental challenges such as ultraviolet radiation. These outcomes were confirmed by in-vitro genetic testing on a reconstructed human skin model. Conclusion: The studies allowed us to identify and group results in four main skin functions that were significantly enhanced following the application of the Formulation: firmness, hydration, radiance and soothing.

DNA Damage and Repair of Two Ecotypes of Phragmites communis Subjected to Water Stress

In order to thoroughly understand the mechanism Of drought resistance in plants at DNA level, the DNA damage of two ecotypes of reeds (Phragmites communis T.) stressed by PEG 6000 was analyzed by means of fluorescence analysis of DNA unwinding (FADU). The results showed that the residual double strand DNA percentages (dsDNA%) in dune reed (DR) were significantly higher than those in swamp reed (SR) treated with either 20% or 30% PEG 6000. This meant that the DNA of DR was less damaged in comparison with SR. Similarly, DR resisted DNA damage more strongly than SR as reactive oxygen species (ROS) increased by adding ROS producers diethyldithio carbamate (DDC), H2O2 and Fe2+ of different concentrations. Meanwhile, treating PEG stressed SR with ROS scavengers such as dimethyl sulphoxide (DMSO) and ascorbic acid (Vc) resulted in the reduction of DNA damage, suggesting that ROS could cause DNA damage. In addition, the DNA repair for water-stressed reeds indicated that DR repaired DNA damage much faster and more completely. This might be the first indication that drought stress led to DNA damage in plants and that drought resistance of plants was closely related to DNA damage and repair.

Regulation of DNA double-strand break repair pathway choice

DNA double-strand breaks （DSBs） are critical lesions that can result in cell death or a wide variety of genetic alterations including largeor small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining （NHEJ） and homologous recombination （HR）, and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1（XRS2） complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit （DNA-PKcs）, and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM.

Homologous recombination in DNA repair and DNA damage tolerance

Homologous recombination （HR） comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks （DSBs） and interstrand crosslinks （ICLs）. In addition, recombination provides critical support for DNA replication in the recovery of stalled or broken replication forks, contributing to tolerance of DNA damage. A central core of proteins, most critically the RecA homolog Rad51, catalyzes the key reactions that typify HR： homology search and DNA strand invasion. The diverse functions of recombination are reflected in the need for context-specific factors that perform supplemental functions in conjunction with the core proteins. The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and contributes to cancer etiology. Mutations in the BRCA2 recombination gene cause predisposition to breast and ovarian cancer as well as Fanconi anemia, a cancer predisposition syndrome characterized by a defect in the repair of DNA interstrand crosslinks. The cellular functions of recombination are also germane to DNA-based treatment modalities of cancer, which target replicating cells by the direct or indirect induction of DNA lesions that are substrates for recombination pathways. This review focuses on mechanistic aspects of HR relating to DSB and ICL repair as well as replication fork support.

A brief history of the DNA repair field

The history of the repair of damaged DNA can be traced to the mid-1930s. Since then multiple DNA repair mechanisms, as well as other biological responses to DNA damage, have been discovered and their regulation has been studied. This article briefly recounts the early history of this field.

Effects of temperature on UV-B-induced DNA damage and photorepair in Arabidopsis thaliana

DNA damage in the form of cyclobutane pyrimidine dimers(CPDs) and (6-4) photoproducts(6-4PPs) induced by UV-B radiation in Arabidopsis thaliana at different temperatures was investigated using ELISA with specific monoclonal antibodies. CPDs and 6-4PPs increased during 3 h UV-B exposure, but further exposure led to decreases. Contrary to the commonly accepted view that DNA damage induced by UV-B radiation is temperature-independent because of its photochemical nature, we found UV-B-induction of CPDs and 6-4PPs in Arabidopsis to be slower at a low than at a high temperature. Photorepair of CPDs at 24℃ was much faster than that at 0℃ and 12℃, with 50% CPDs removal during 1 h exposure to white light. Photorepair of 6-4PPs at 12℃ was very slow as compared with that at 24℃, and almost no removal of 6-4PPs was detected after 4 h exposure to white light at 0℃. There was evidence to suggest that temperature-dependent DNA damage and photorepair could have important ecological implications.

Assessment of Human DNA Repair (NER) Capacity With DNA Repair Rate (DRR) by Comet Assay

Objective Alkaline comet assay was used to evaluate DNA repair (nucleotide excision repair, NER) capacity of human fresh lymphocytes from 12 young healthy non-smokers (6 males and 6 females). Methods Lymphocytes were exposed to UV-C (254 nm) at the dose rate of 1.5 J/m2/sec. Novobiocin (NOV) and aphidicolin (APC), DNA repair inhibitors, were utilized to imitate the deficiency of DNA repair capacity at the incision and ligation steps of NER. Lymphocytes from each donor were divided into three grougs: UVC group, UVC plus NOV group, and UVC plus APC group. DNA single strand breaks were detected in UVC irradiated cells incubated for 0, 30, 60, 90, 120, 180, and 240 min after UVC irradiation. DNA repair rate (DRR) served as an indicator of DNA repair capacity. Results The results indicated that the maximum DNA damage (i.e. maximum tail length) in the UVC group mainly appeared at 90 min. The ranges of DRRs in the UVC group were 62.84%-98.71%. Average DRR value was 81.84%. The DRR difference between males and females was not significant (P<0.05). However, the average DRR value in the UVC plus NOV group and the UVC plus APC group was 52.98% and 39.57% respectively, which were significantly lower than that in the UVC group (P<0.01). Conclusion The comet assay is a rapid, simple and sensitive screening test to assess individual DNA repair (NER) capacity. It is suggested that the time to detect DNA single strand breaks in comet assay should include 0 (before UV irradiation), 90 and 240 min after exposure to 1.5 J·m-2 UVC at least. The DRR, as an indicator, can represent the individual DNA repair capacity in comet assay.

New insights into estrogenic regulation of O^6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells： Co-degradation of ER-α and MGMT proteins by fulvestrant or O^6-benzylguanine indicates fresh avenues for therapy

Endocrine therapy using estrogen receptor-u （ER-α） antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O^6-methylguanine DNA methyltransferase （MGMT）, a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines （MCF-7, T47D） and ER- negative cell lines （MDAMB- 468, MDAMB-231）, and established inhibitors of ER-α and MGMT, namely, ICI-182,780 （Faslodex） and O^6- benzylguanine, respectively, were used to study MGMT- ER interactions. The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements （EREs） and two antioxidant-responsive elements （AREs）. MGMT expression was upregulated by estrogen, downregulated by tamoxifen in Western blot and promoter-linked reporter assays. Similarly, both transient and stable transfections of Nrf-2 （nuclear factor-erythroid 2-related factor-2） increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this dragresistance determinant. Of the different ER-α antagonists tested, the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose, time and ER-α dependent manner, similar to O^6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O^6-benzylguanine also induced a specific loss of ER-a and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-a and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-a proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced the cytotoxicity of MGMT-targeted alkylating agents, namely, temozolomide and BCNU by 3 to 4-fold in ER-α positive cells, but not in ER-negative cells. We conclude that MGMT and ER-α proteins exist as a complex and are co-targeted for ubiquitin-conjugation and subsequent proteasomal degradation. The findings offer a clear rationale for combining alkylating agents with endocrine therapy.

DNA polymerase zeta （pol ζ） in higher eukaryotes

Most current knowledge about DNA polymerase zeta （pol ζ） comes from studies of the enzyme in the budding yeast Saccharomyces cerevisiae, where pol ζ consists of a complex of the catalytic subunit Rev3 with Rev7, which associates with Revl. Most spontaneous and induced mutagenesis in yeast is dependent on these gene products, and yeast pol can mediate translesion DNA synthesis past some adducts in DNA templates. Study of the homologous gene products in higher eukaryotes is in a relatively early stage, but additional functions for the eukaryotic proteins are already apparent. Suppression of vertebrate REV3L function not only reduces induced point mutagenesis but also causes larger-scale genome instability by raising the frequency of spontaneous chromosome translocations. Disruption of Rev3L function is tolerated in Drosophila, Arabidopsis, and in vertebrate cell lines under some conditions, but is incompatible with mouse embryonic development. Functions for REV3L and REV7（MAD2B） in higher eukaryotes have been suggested not only in translesion DNA synthesis but also in some forms of homologous recombination, repair of interstrand DNA crosslinks, somatic hypermutation of immunoglobulin genes and cell-cycle control. This review discusses recent developments in these areas.

DNA repair and synthetic lethality

Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particular homologous recombination （HR）, are highly sensitive to DNA-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly （adenosine diphosphate （ADP）-ribose） polymerase （PARP） inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR-defective tumor cells.

DNA polymorphism and risk of esophageal squamous cell carcinoma in a population of North Xinjiang,China

AIM:To investigate the role of metabolic enzyme and DNA repair genes in susceptibility of esophageal squamous cell carcinoma(ESCC). METHODS:A case-control study was designed with 454 samples from 128 ESCC patients and 326 gender, age and ethnicity-matched control subjects.Genotypes of 69 single nucleotide polymorphisms(SNPs)of metabolic enzyme(aldehyde dehydrogenase-2,ALDH2; alcohol dehydrogenase-1 B,ADHB1;Cytochrome P450 2A6,CYP2A6)and DNA repair capacity genes(excision repair cross complementing group 1,ERCC1; O 6-methylguanine DNA methyltransferase,MGMT; xeroderma pigmentosum group A,XPA;xeroderma pigmentosum group A,XPD)were determined by the Sequenom MassARRAY system,and results were analyzed using unconditional logistic regression adjusted for age,gender. RESULTS:There was no association between the variation in the ERCC1,XPA,ADHB1 genes and ESCC risk.Increased risk of ESCC was suggested in ALDH2 for frequency of presence C allele of SNP [Rs886205:1.626(1.158-2.284)],XPD for C allele [Rs50872:1.482(1.058-2.074)],and MGMT for A allele[Rs11016897:1.666(1.245-2.228)].Five variants of MGMT were associated with a protective effect on ESCC carcinogenesis,including C allele [Rs7069143:0.698(0.518-0.939)],C allele[Rs3793909: 0.6 5 3(0.4 2 9-0.9 9 5)],A a l l e l e[R s 1 2 7 7 1 8 8 2: 0.719(0.524-0.986)],C allele[Rs551491:0.707 (0.529-0.945)],and A allele[Rs7071825:0.618 (0.506-0.910)].At the genotype level,increased risk of ESCC carcinogenesis was found in homozygous carriers of the ALDH2 Rs886205[CC vs TT,odds ratios(OR): 3.116,95%CI:1.179-8.234],MGMT Rs11016879(AA vs GG,OR:3.112,95%CI:1.565-6.181),Rs12771882 (AA vs GG,OR:2.442,95%CI:1.204-4.595),and heterozygotes carriers of the ALDH2 Rs886205 (CT vs TT,OR:3.930,95%CI:1.470-10.504), MGMT Rs11016879(AG vs GG,OR:3.933,95%CI: 2.216-6.982)and Rs7075748(CT vs CC,OR:1.949, 95%CI:1.134-3.350),respectively.Three variants were associated with a protective effect on ESCC carcinogenesis,carriers of the MGMT Rs11016878(AG vs AA,OR:0.388,95%CI:0.180-0.836),Rs7069143(CT vs CC,OR:0.478,95%CI:0.303-0.754)and Rs7071825(GG vs AA,OR:0.493,95%CI:0.266-0.915). Increased risk of ESCC metastasis was indicated in MGMT for frequency of presence C allele[Rs7068306: 2.204(1.244-3.906)],A allele[Rs10734088:1.968 (1.111-3.484)]and C allele[Rs4751115:2.178(1.251-3.791)].Two variants in frequency of presence C allele of CYP2A6[Rs8192720:0.290(0.099-0.855)] and A allele of MGMT[Rs2053139:0.511(0.289-0.903)] were associated with a protective effect on ESCC progression.Increased risk of ESCC metastasis was found in heterozygote carriers of the MGMT Rs7068306 (CG vs CC,OR:4.706,95%CI:1.872-11.833).CONCLUSION:Polymorphic variation in ALDH2,XPD and MGMT genes may be of importance for ESCC susceptibility.Polymorphic variation in CYP2A6 and MGMT are associated with ESCC metastasis.

Expression of DNA-dependent protein kinase in human granulocytes

Human polymorphonuclear leukocytes (PMN) have been reported to completely lack of DNA-dependent protein kinase (DNA-PK) which is composed of Ku protein and the catalytic subunit DNA-PKcs, needed for nonhomologous end-joining (NHEJ) of DNA double-strand breaks. Promyelocytic HL-60 cells express a variant form of Ku resulting in enhanced radiation sensitivity. This raises the question if low efficiency of NHEJ, instrumental for the cellular repair of oxidative damage, is a normal characteristic of myeloid differentiation. Here we confirmed the complete lack of DNAPK in P MN protein extracts, and the expression of the truncated Ku86 variant form in HL-60. However, this degradation of DNA-PK was shown to be due to a DNA-PK-degrading protease in PMN and HL-60. In addition, by using a protease-resistant whole cell assay, both Ku86 and DNA-PKcs could be demonstrated in PMN, suggesting the previously reported absence in PMN of DNA-PK to be an artefact. The levels of Ku86 and DNA-PKcs were much reduced in PMN, as compared with that of the lymphocytes, whereas HL-60 displayed a markedly elevated DNA-PK concentration.In conclusion, our findings provide evidence of reduced, not depleted expression of DNA-PK during the mature stages of myeloid differentiation.

Helicobacter pylori infection and expression of DNA mismatch repair proteins

AIM： TO determine the expression of DNA （MMR） proteins, including hMLH1 and hMSH2, in gastric epithelial cells in the patients with or without Helicobacter pylori （H pylori）-infected gastritis. METHODS： Fifty Hpylori-positive patients and 50 H pylori-negative patients were enrolled in the study. During endoscopy of patients with non-ulcer dyspepsia, two antral and two corpus biopsies were taken for histological examination （Giemsa stain） and for immunohistochemical staining of hMLH1 and hMSH2. RESULTS： The percentage of epithelial cell nuclei that demonstrated positivity for hMLH1 staining was 84.14 ± 7.32% in Hpylori-negative patients, while it was 73.34 ±10.10% in Hpylori-positive patients （P 〈 0.0001）. No significant difference was seen between the two groups regarding the percentage of epithelial cell nuclei that demonstrated positivity for hMSH2 staining （81.16±8.32% in H pylori-negative versus 78.24 ± 8.71% in Hpylori-positive patients; P = 0.09）. CONCLUSION： This study indicates that Hpylori might promote development of gastric carcinoma at least in part through its ability to affect the DNA MMR system

Evolving insights:how DNA repair pathways impact cancer evolution

Viewing cancer as a large,evolving population of heterogeneous cells is a common perspective.Because genomic instability is one of the fundamental features of cancer,this intrinsic tendency of genomic variation leads to striking intratumor heterogeneity and functions during the process of cancer formation,development,metastasis,and relapse.With the increased mutation rate and abundant diversity of the gene pool,this heterogeneity leads to cancer evolution,which is the major obstacle in the clinical treatment of cancer.Cells rely on the integrity of DNA repair machineries to maintain genomic stability,but these machineries often do not function properly in cancer cells.The deficiency of DNA repair could contribute to the generation of cancer genomic instability,and ultimately promote cancer evolution.With the rapid advance of new technologies,such as single-cell sequencing in recent years,we have the opportunity to better understand the specific processes and mechanisms of cancer evolution,and让s relationship with DNA repair.Here,we review recent findings on how DNA repair affects cancer evolution,and discuss how these mechanisms provide the basis for critical clinical challenges and therapeutic applications.

Association Between Polymorphisms of DNA Repair Gene XRCC1 and DNA Damage in Asbestos-Exposed Workers

Objective To compare the asbestos-induced DNA damage and repair capacities of DNA damage between 104 asbestosexposed workers and 101 control workers in Qingdao City of China and to investigate the possible association between polymorphisms in codon 399 of XRCC1 and susceptibility to asbestosis. Methods DNA damage levels in peripheral blood lymphocytes were determined by comet assay, and XRCC1 genetic polymorphisms of DNA samples from 51 asbestosis cases and 53 non-asbestosis workers with a similar asbestos exposure history were analyzed by PCR/RFLP. Results The basal comet scores （3.95±2.95） were significantly higher in asbestos-exposed workers than in control workers （0.10±0.28）. After 1 h H2O2 stimulation, DNA damage of lymphocytes exhibited different increases. After a 4 h repair period, the comet scores were 50.98±19.53 in asbestos-exposed workers and 18.32±12.04 in controls. The residual DNA damage （RD） was significantly greater （P〈0.01） in asbestos-exposed workers （35.62%） than in controls （27.75%）. XRCC1 genetic polymorphism in 104 asbestos-exposed workers was not associated with increased risk of asbestosis. But compared with polymorphisms in the DNA repair gene XRCC1 （polymorphisms in codon 399） and the DNA damage induced by asbestos, the comet scores in asbestosis cases with Gin/Gin, Gln/Arg, and Arg/Arg were 40.26±18.94, 38.03±28.22, and 32.01±11.65, respectively, which were higher than those in non-asbestosis workers with the same genotypes （25.58±11.08, 37.08±14.74, and 29.38±10.15）. There were significant differences in the comet scores between asbestosis cases and non-asbestosis workers with Gin/Gin by Student＇s t-test （P〈0.05 or 0.01）. The comet scores were higher in asbestosis workers with Gin/Gin than in those with Arg/Arg and in non-asbestosis workers exposed to asbestos, but without statistically significant difference. Conclusions Exposure to asbestos may be related to DNA damage or the capacity of cells to repair H2O2-induced DNA damage. DNA repair gene XRCC 1 codon 399 may be responsible for the inter-individual susceptibility in DNA damage and repair capacities.

SET8 Inhibition Potentiates Radiotherapy by Suppressing DNA Damage Repair in Carcinomas

Objective SET8 is a member of the SET domain-containing family and the only known lysine methyltransferase(KMT)that monomethylates lysine 20 of histone H4(H4 K20 me1).SET8 has been implicated in many essential cellular processes,including cell cycle regulation,DNA replication,DNA damage response,and carcinogenesis.There is no conclusive evidence,however,regarding the effect of SET8 on radiotherapy.In the current study we determined the efficacy of SET8 inhibition on radiotherapy of tumors and the underlying mechanism.Methods First,we explored the radiotherapy benefit of the SET8 expression signature by analyzing clinical data.Then,we measured a series of biological endpoints,including the xenograft tumor growth in mice and apoptosis,frequency of micronuclei,and foci of 53 BP1 andγ-H2 AX in cells to detect the SET8 effects on radiosensitivity.RNA sequencing and subsequent experiments were exploited to verify the mechanism underlying the SET8 effects on radiotherapy.Results Low expression of SET8 predicted a better benefit to radiotherapy in lung adenocarcinoma(LUAD)and invasive breast carcinoma(BRCA)patients.Furthermore,genetic deletion of SET8 significantly enhanced radiation treatment efficacy in a murine tumor model,and A549 and MCF7 cells;SET8 overexpression decreased the radiosensitivity.SET8 inhibition induced more apoptosis,the frequency of micronuclei,and blocked the kinetics process of DNA damage repair as 53 BP1 andγ-H2 AX foci remained in cells.Moreover,RNF8 was positively correlated with the SET8 impact on DNA damage repair.Conclusion Our results demonstrated that SET8 inhibition enhanced radiosensitivity by suppressing DNA damage repair,thus suggesting that SET8 potentiated radiotherapy of carcinomas.As new inhibitors of SET8 are synthesized and tested in preclinical and clinical settings,combining SET8 inhibitors with radiation warrants consideration for precise radiotherapy.

Dynamic Changes in DNA Damage and Repair Biomarkers with Employment Length among Nickel Smelting Workers

Our study explored the dynamic changes in andthe relationship between the DNA damage marker8-hydroxy-2＇-deoxyguanosine （8-OHdG） and theDNA repair marker 8-hydroxyguanine DNAglycosidase 1 （hOGG1） according to the length ofoccupational employment in nickel smeltingworkers. One hundred forty nickel-exposedsmelting workers and 140 age-matched unexposedoffice workers were selected from the Jinchangcohort. The 8-OHdG levels in smelting workers wassignificantly higher than in office workers （Z=-8.688,P〈0.05） and the 8-OHdG levels among nickelsmelting workers in the 10-14 y employment lengthcategory was significantly higher than among allpeers. The hOGG1 levels among smelting workerswere significantly lower than those of non-exposedworkers （Z=-8.948, P〈0.05）. There were significantdifferences between employment length andhOGG1 levels, with subjects employed in nickelsmelting for 10-14 y showing the highest levels ofhOGG1. Correlation analysis showed positivecorrelations between 8-OHdG and hOGG1 levels（r=0.413; P〈0.01）. DNA damage was increased withemployment length among nickel smelting workersand was related to the inhibition of hOGG1 repaircapacity.