Association of DNA Base-excision Repair XRCC1, OGG1 and APE1 Gene Polymorphisms with Nasopharyngeal Carcinoma Susceptibility in a Chinese Population

Li, Qing,Wang, Jian-Min,Peng, Yu,Zhang, Shi-Heng,Ren, Tao,Luo, Hao,Cheng, Yi,Wang, Dong Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.9

Background: Numerous carcinogens and reactive oxygen species (ROS) may cause DNA damage including oxidative base lesions that lead to risk of nasopharyngeal carcinoma. Genetic susceptibility has been reported to play a key role in the development of this disease. The base excision repair (BER) pathway can effectively remove oxidative lesions, maintaining genomic stability and normal expression, with X-ray repair crosscomplementing1 (XRCC1), 8-oxoguanine glycosylase-1 (OGG1) and apurinic/apyimidinic endonuclease 1 (APE1) playing important roles. Aims: To analyze polymorphisms of DNA BER genes (OOG1, XRCC1 and APE1) and explore their associations, and the combined effects of these variants, with risk of nasopharyngeal carcinoma. Materials and Methods: We detected SNPs of XRCC1 (Arg399Gln), OGG1 (Ser326Cys), APE1 (Asp148Glu and -141T/G) using the polymerase chain reaction (PCR) with peripheral blood samples from 231 patients with NPC and 300 healthy people, furtherly analyzing their relations with the risk of NPC in multivariate logistic regression models. Results: After adjustment for sex and age, individuals with the XRCC1 399Gln/Gln (OR=1.96; 95%CI:1.02-3.78; p=0.04) and Arg/Gln (OR=1.87; 95%CI:1.29-2.71; p=0.001) genotype variants demonstrated a significantly increased risk of nasopharyngeal carcinoma compared with those having the wild-type Arg/Arg genotype. APE1-141G/G was associated with a significantly reduced risk of NPC (OR=0.40;95%CI:0.18-0.89) in the smoking group. The OR calculated for the combination of XRCC1 399Gln and APE1 148Gln, two homozygous variants, was significantly additive for all cases (OR=2.09; 95% CI: 1.27-3.47; p=0.004). Conclusion: This is the first study to focus on the association between DNA base-excision repair genes (XRCC1, OGG1 and APE1) polymorphism and NPC risk. The XRCC1 Arg399Gln variant genotype is associated with an increased risk of NPC. APE1-141G/G may decrease risk of NPC in current smokers. The combined effects of polymorphisms within BER genes of XRCC1 399Gln and APE1 148Gln may contribute to a high risk of nasopharyngeal carcinoma.

Novel mechanism of base excision repair inhibition by low-dose nickel(II): interference of p53-mediated APE1 function

Kim Hye Lim,Kim Yeo Jin,기남국,Koedrith Preeyaporn,서영록 대한독성 유전단백체 학회 2021 Molecular & cellular toxicology Vol.17 No.2

Backgrounds Nickel is known as a carcinogen through the environmental and occupational exposures. One of carcinogenic mechanisms of nickel is an induction of oxidative stresses and inhibition of DNA repair. But the exact molecular mechanisms by which nickel induces carcinogenicity remains unclear. Objectives We selected the sub-lethal dose of nickel in human cells using MTT assay and FACS analysis. To demonstrate the effect of nickel on transcriptional activity of p53, we conducted an electrophoretic mobility shift assay and streptavidin magnetic bead assay. Gadd45a–APE1 complex was confirmed by in situ proximity ligation assay. Results We demonstrated that nickel can interfere with the physical interaction between Gadd45a and APE1, in vitro and in situ, as well as APE1 activity in vitro. Conclusion Our study implies that the inhibition of p53-mediated APE1 activity in base excision repair might be suggested as one of the potential carcinogenic mechanisms in response to nickel even at a low dose. Backgrounds Nickel is known as a carcinogen through the environmental and occupational exposures. One of carcinogenic mechanisms of nickel is an induction of oxidative stresses and inhibition of DNA repair. But the exact molecular mechanisms by which nickel induces carcinogenicity remains unclear. Objectives We selected the sub-lethal dose of nickel in human cells using MTT assay and FACS analysis. To demonstrate the effect of nickel on transcriptional activity of p53, we conducted an electrophoretic mobility shift assay and streptavidin magnetic bead assay. Gadd45a–APE1 complex was confirmed by in situ proximity ligation assay. Results We demonstrated that nickel can interfere with the physical interaction between Gadd45a and APE1, in vitro and in situ, as well as APE1 activity in vitro. Conclusion Our study implies that the inhibition of p53-mediated APE1 activity in base excision repair might be suggested as one of the potential carcinogenic mechanisms in response to nickel even at a low dose.

Enhancement of Methyl Methanesulfonate-Induced Base Excision Repair in the Presence of Selenomethionine on p53-Dependent Pathway

Jung, Hwa-Jin,Lee, Ju-Han,Seo, Young-R. The Korean Society of Food Science and Nutrition 2009 Journal of medicinal food Vol.12 No.2

Selenomethionine (SeMet) has been identified as a chemopreventive antioxidant to activate p53-mediated nucleotide excision repair. In this study, we examined whether p53-mediated base excision repair (BER) might be induced by SeMet. When methyl methanesulfonate, a BER-inducing agent, was treated in the cells, DNA damage was rapidly decreased in the presence of SeMet. In addition, our data showed that the removal of apurinic/apyrimidinic sites was significantly enhanced in the presence of SeMet. Furthermore, we observed that the expression of gadd45a, known to involve BER as one of the p53 downstream genes, was increased by SeMet in p53 wild-type RKO cells. Those results supported the proposal that BER activity might be dependent on wild-type p53 under the modulation of gadd45a expression in response to SeMet. We suggested that p53-dependent BER activity as a distinct mechanism of SeMet might play an important role to prevent cancer caused by various oxidative stresses.

Enhancement of Methyl Methanesulfonate-Induced Base Excision Repair in the Presence of Selenomethionine on p53-Dependent Pathway

Hwa Jin Jung,Ju Han Lee,서영록 한국식품영양과학회 2009 Journal of medicinal food Vol.12 No.2

Selenomethionine (SeMet) has been identified as a chemopreventive antioxidant to activate p53-mediated nucleotide excision repair. In this study, we examined whether p53-mediated base excision repair (BER) might be induced by SeMet. When methyl methanesulfonate, a BER-inducing agent, was treated in the cells, DNA damage was rapidly decreased in the presence of SeMet. In addition, our data showed that the removal of apurinic/apyrimidinic sites was significantly enhanced in the presence of SeMet. Furthermore, we observed that the expression of gadd45a, known to involve BER as one of the p53 downstream genes, was increased by SeMet in p53 wild-type RKO cells. Those results supported the proposal that BER activity might be dependent on wild-type p53 under the modulation of gadd45a expression in response to SeMet. We suggested that p53-dependent BER activity as a distinct mechanism of SeMet might play an important role to prevent cancer caused by various oxidative stresses.

Single Nucleotide Polymorphisms of DNA Base-excision Repair Genes (APE1, OGG1 and XRCC1) Associated with Breast Cancer Risk in a Chinese Population

Luo, Hao,Li, Zheng,Qing, Yi,Zhang, Shi-Heng,Peng, Yu,Li, Qing,Wang, Dong Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.3

Altered DNA repair capacity can result in increased susceptibility to cancer. The base excision repair (BER) pathway effectively removes DNA damage caused by ionizing radiation and reactive oxidative species (ROS). In the current study, we analyzed the possible relation of polymorphisms in BER genes, including 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1), and X-ray repair cross-complementing group 1 protein (XRCC1), with breast cancer risk in Chinese Han women. This case-control study examined 194 patients with breast cancer and 245 cancer-free hospitalized control subjects. Single nucleotide polymorphisms (SNPs) of OGG1 (Ser326Cys), XRCC1 (Arg399Gln), and APE1 (Asp148Glu and -141T/G) were genotyped and analyzed for their association with breast cancer risk using multivariate logistic regression models. We found that XRCC1 Arg399Gln was significantly associated with an increased risk of breast cancer. Similarly, the XRCC1 Gln allele was significantly associated with an elevated risk in postmenopausal women and women with a high BMI (${\geq}24kg/m^2$). The OGG1 Cys allele provided a significant protective effect against developing cancer in women with a low BMI (< $24kg/m^2$). When analyzing the combined effects of these alleles on the risk of breast cancer, we found that individuals with ${\geq}2$ adverse genotypes (XRCC1 399Gln, APE1 148Asp, and OGG1 326Ser) were at a 2.18-fold increased risk of breast cancer (P = 0.027). In conclusion, our data indicate that Chinese women with the 399Gln allele of XRCC1 have an increased risk of breast cancer, and the combined effects of polymorphisms of BER genes may contribute to tumorigenesis.

항종양 인자 p53에 의해서 유도되는 Base Excision Repair (BER)에 관한 연구: DNA Polymerase Beta의 전사적 활성화를 중심으로

서영록,정화진 대한암예방학회 2006 Journal of cancer prevention Vol.11 No.2

BER activity has been known to increase when DNA damage is induced by ionizing radiation (IR), simple alkylating agents, as well as free radicals exposed by endogenous hydrolytic and oxidative processes. The DNA polymerase beta enzyme as an important component of BER pathway, fills in the incised repair patch and participates in removing the overhang created by the displaced strand when treated the alkylating agent such as methyl methanesulfonate (MMS). Recent work has demonstrated that the p53 affects the stability of DNA polymerase beta and apurinic/apyrimidinic (AP) endonuclease interaction although it is not known whether the expression of DNA polymerase beta is regulated by p53 or not. Our data showed that a critical participator of BER activity, DNA polymerase beta can be overexpressed in the wild-type p53 background. We also found that the consensus p53 binding site in the promoter of DNA polymerase beta gene, indicating that the DNA polymerase beta might be transcriptionally regulated by p53. The regulation mechanism of DNA polymerase beta at the transcription level as well as protein interaction between p53 and DNA polymerase beta will provide the potential evidence how repair proteins are regulated to restore DNA damage induced by the environmental carcinogenesis. (Cancer Prev Res 11, 107-113, 2006)

Sensitive base excision repair enzyme activity assay utilizing pyrrolo-dC modified duplex DNA as a novel probe

Chang Yeol LEE,Ki Soo PARK,Hyun Gyu PARK 한국생물공학회 2017 한국생물공학회 학술대회 Vol.2017 No.10

A novel chemopreventive mechanism of selenomethionine: Enhancement of APE1 enzyme activity via a Gadd45a, PCNA and APE1 protein complex that regulates p53-mediated base excision repair

JUNG, HWA JIN,KIM, HYE LIM,KIM, YEO JIN,WEON, JONG-IL,SEO, YOUNG ROK D.A. Spandidos 2013 ONCOLOGY REPORTS Vol.30 No.4

<P>Organic selenium compounds have been documented to play a role in cancer prevention. Our previous study showed that selenomethionine (SeMet) induces p53 activation without genotoxic effects including apoptosis and cell cycle arrest. In this study, we investigated the mechanism by which organic selenium compounds promote p53-mediated base excision repair (BER) activity. Our data demonstrated for the first time that the interaction between growth arrest and DNA damage-inducible protein 45A (Gadd45a), which is a p53-activated downstream gene, and two BER-mediated repair proteins, proliferating cell nuclear antigen (PCNA) and apurinic/apyrimidinic endonuclease (APE1/Ref-1), was significantly increased in a p53-dependent manner following treatment with organic selenium compounds. Furthermore, we observed that the activity of APE1 was significantly increased in a p53-dependent manner in response to the organic selenium compounds. These results suggest that BER activity is dependent on wild-type p53 activity and is mediated by the modulation of protein interactions between Gadd45a and repair proteins in response to organic selenium compounds. We propose that p53-dependent BER activity is a distinct chemopreventive mechanism mediated by organic selenium compounds, and that this may provide insight into the development of effective chemopreventive strategies against various oxidative stresses that contribute to a variety of human diseases, particularly cancer.</P>

The tumor suppressor homolog in fission yeast, myh1⁺, displays a strong interaction with the checkpoint gene rad1⁺

Jansson, K.,Warringer, J.,Farewell, A.,Park, H.O.,Hoe, K.L.,Kim, D.U.,Hayles, J.,Sunnerhagen, P. Elsevier 2008 Mutation research Vol.644 No.1

The DNA glycosylase MutY is strongly conserved in evolution, and homologs are found in most eukaryotes and prokaryotes examined. This protein is implicated in repair of oxidative DNA damage, in particular adenine mispaired opposite 7,8-dihydro-8-oxoguanine. Previous investigations in Escherichia coli, fission yeast, and mammalian cells show an association of mutations in MutY homologs with a mutator phenotype and carcinogenesis. Eukaryotic MutY homologs physically associate with several proteins with a role in replication, DNA repair, and checkpoint signaling, specifically the trimeric 9-1-1 complex. In a genetic investigation of the fission yeast MutY homolog, myh1<SUP>+</SUP>, we show that the myh1 mutation confers a moderately increased UV sensitivity alone and in combination with mutations in several DNA repair genes. The myh1 rad1, and to a lesser degree myh1 rad9, double mutants display a synthetic interaction resulting in enhanced sensitivity to DNA damaging agents and hydroxyurea. UV irradiation of myh1 rad1 double mutants results in severe chromosome segregation defects and visible DNA fragmentation, and a failure to activate the checkpoint. Additionally, myh1 rad1 double mutants exhibit morphological defects in the absence of DNA damaging agents. We also found a moderate suppression of the slow growth and UV sensitivity of rhp51 mutants by the myh1 mutation. Our results implicate fission yeast Myh1 in repair of a wider range of DNA damage than previously thought, and functionally link it to the checkpoint pathway.

Sensitive Assay of Base Excision Repair Enzyme Activity Using Fluorescent G-quadruplex Probe

Chang Yeol LEE,Ki Soo PARK,Yujin JUNG,Hyun Gyu PARK 한국생물공학회 2015 한국생물공학회 학술대회 Vol.2015 No.10