8 Hydroxyguanine

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Hiroshi Kasai - One of the best experts on this subject based on the ideXlab platform.

  • Measurement of 8-Hydroxyguanine as an oxidative stress biomarker in saliva by HPLC-ECD
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Kazuaki Kawai, Hiroshi Kasai, Yuya Kawasaki, Shintaro Watanabe, Masanori Ohta, Toru Honda, Hiroshi Yamato
    Abstract:

    Abstract Introduction Oxidative stress leads to many kinds of diseases. Currently, urinary 8-hydroxydeoxyguanosine (8-OHdG) is widely measured as an oxidative stress biomarker. There is a specific advantage if saliva can be used as the sample to measure the oxidative stress biomarker, because saliva is much easier to collect than urine. In this study, we investigated the measurement of 8-Hydroxyguanine (8-OHGua) as an oxidative stress marker in saliva, by a column switching HPLC system equipped with an electrochemical detector (HPLC-ECD). Findings The 8-OHGua in saliva could be detected as a single peak by HPLC-ECD. The average level of 8-OHGua in saliva was 3.80 ng/mL in ordinary, non-smoking subjects. The salivary 8-OHGua levels of smokers were significantly higher than those of non-smokers. Conclusions Salivary 8-OHGua may be a useful noninvasive and promising oxidative stress biomarker

  • Carcinogenesis vol.17 no.ll pp.2419-2422, 1996 Increased
    2016
    Co-Authors: Raizo Yamaguchi, Takeshi Hirano, Myung Hee Chung, Shinya Asami, Atsuo Sugita, Hiroshi Kasai
    Abstract:

    8-Hydroxyguanine levels in DNA and its repair activity in rat kidney after administration of a renal carcinogen, ferric nitrilotriacetat

  • chronic alcohol consumption prevents 8 Hydroxyguanine accumulation in 3 methyl 4 dimethylaminoazobenzene treated mouse liver
    Biochemical and Biophysical Research Communications, 2009
    Co-Authors: Takkeshi Hirano, Yuko Ootsuyama, Akinori Sakai, Hiroshi Kasai
    Abstract:

    Alcohol consumption is known to have opposing effects on carcinogenesis: promotion and prevention. In this study, we examined the effects of 12% ethanol on oxidative DNA damage accumulation and its repair in mouse livers treated with 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), a well-known hepatic carcinogen. We previously reported that 3'-MeDAB increased 8-Hydroxyguanine (8-OH-Gua) accumulation and its repair activity, accompanied by the fragmentation of 8-oxoguanine DNA glycosylase 1 (OGG1), the main repair enzyme of 8-OH-Gua. The present results showed that 12% ethanol intake attenuated the 8-OH-Gua accumulation, but not the fragmentation of OGG1 induced by 3'-MeDAB. Additionally, no significant changes in oxidative status, as monitored by lipid peroxidation (LPO), were observed among the 3'-MeDAB-treated mouse livers with/without alcohol administration. These findings suggested that 12% ethanol consumption may reduce the risk of 3'-MeDAB-induced carcinogenesis by decreasing 8-OH-Gua accumulation.

  • urinary 8 Hydroxyguanine may be a better marker of oxidative stress than 8 hydroxydeoxyguanosine in relation to the life spans of various species
    Antioxidants & Redox Signaling, 2006
    Co-Authors: Peter Svoboda, Kazuaki Kawai, Muneyuki Maekawa, Toshikazu Tominaga, Kirsti Savela, Hiroshi Kasai
    Abstract:

    Oxidative DNA damage is believed to be involved in the aging process. Species with shorter potential life spans generally have a higher specific metabolic rate (SMR), and would be expected to have increased levels of oxidative stress and DNA damage, as compared to long-lived species. An automatized HPLC method based on electrochemical detection was used to measure the levels of the oxidative DNA damage markers 8-hydroxydeoxyguanosine (8-OH-dG) and 8-Hydroxyguanine (8-OH-Gua) in urinary samples from mammals with various potential life spans (mice, rats, guinea pigs, cats, chimpanzees, and humans). There was no significant linear correlation (r = -0.71, p = 0.11) between the species' potential life spans (log transformed) and the urinary levels of 8-OH-dG as normalized to creatinine (8-OH-dG/creatinine), although the species with longer life spans, such as chimpanzee and human, had among the lowest levels detected. In contrast, the negative linear correlation between the species' potential life span (log transformed) and the urinary levels of 8-OH-Gua as normalized to creatinine (8-OH-Gua/creatinine), was significant (r = -0.97, p = 0.002). In addition, there was a positive linear and significant correlation between SMR and 8-OH-dG/creatinine (r = 0.91, p = 0.01) or 8- OH-Gua/creatinine (r = 0.90, p = 0.01). These results suggest that 8-OH-Gua, rather than 8-OH-dG, may be a more general marker for oxidative damage.

  • analysis of 8 Hydroxyguanine 8 oh gua released from dna by the formamidopyrimidine dna glycosylase fpg protein a reliable method to estimate cellular oxidative stress
    Journal of Radiation Research, 2004
    Co-Authors: Hiroshi Orimo, Yoshiki Tokura, Serge Boiteux, Hiroshi Kasai
    Abstract:

    8-OH-Gua background level/Fpg protein/γ-irradiation. To improve the analyses of a form of oxidative DNA damage, 8-Hydroxyguanine (8-OH-Gua), we treated isolated DNA with formamidopyrimidine DNA glycosylase (Fpg) and analyzed the released 8-OH-Gua by using a high-performance liquid chromatography system equipped with an electrochemical detector (HPLC-ECD). The human lung carcinoma cells (A549) and human keratinocyte (HaCaT) were irradiated with γ-rays. After the isolated DNA was treated with the Fpg protein, we analyzed the released 8-OH-Gua by using an HPLC-ECD. With this method, the background level of 8-OH-Gua in DNA from human lung carcinoma cells was determined to be 3.4 residues per 10 7 guanine (Gua). A similar background level of 8-OH-Gua (3.1 residues per 10 7 Gua) was also detected in human keratinocyte DNA with this method. These background 8-OH-Gua levels in cellular DNA are comparable to that obtained previously by an analysis of 8-OH-dGMP after nuclease P1 digestion of cellular DNA (4.3 residues per 10 7 dCMP). A dose-dependent increase of 8-OH-Gua (0.17/10 7 Gua/Gy) was observed after cells were irradiated with γ-rays. Twenty hours after γ-irradiation with 60 Gy, 75% of the 8-OH-Gua produced in keratinocyte DNA was repaired. With our new analysis method, it is possible to detect the small changes in the 8-OH-Gua levels in cellular DNA induced by various environmental factors.

Hiroyuki Kamiya - One of the best experts on this subject based on the ideXlab platform.

  • Action-at-a-Distance Mutagenesis Induced by Oxidized Guanine in Werner Syndrome Protein-Reduced Human Cells
    2015
    Co-Authors: Hiroyuki Kamiya, Daiki Yamazaki, Eri Nakamura, Tetsuaki Makino, Miwako Kobayashi, Ichiro Matsuoka, Hideyoshi Harashima
    Abstract:

    8-Oxo-7,8-dihydroguanine (GO, 8-Hydroxyguanine) in DNA is one of the most important oxidatively damaged bases and causes G:C → T:A substitution mutations. The Werner syndrome protein (WRN) is a cancer-related RecQ DNA helicase and plays many roles in DNA replication and repair. To examine the relationships between GO-induced mutations and WRN, shuttle plasmid DNA containing a GO:C pair in the supF gene was transfected into human U2OS cells, in which WRN was knocked down. The plasmid DNA replicated in the knockdown cells was introduced into an Escherichia coli indicator strain. The knockdown of WRN increased the mutant frequency of the GO-plasmid DNA. Unexpectedly, however, the WRN knockdown only slightly enhanced the targeted G:C → T:A mutation. Instead, base-substitution mutations at various positions were more frequently detected, with statistical significance. The results obtained in this study suggested that the reduction of the cancer-related WRN induced action-at-a-distance mutagenesis by the GO:C pair in human cells. In addition, the WRN knockdown decreased the GO:A-induced A:T → C:G mutations, suggesting that WRN may enhance the mutations caused by GO in the nucleotide pool

  • mutagenicity of secondary oxidation products of 8 oxo 7 8 dihydro 2 deoxyguanosine 5 triphosphate 8 hydroxy 2 deoxyguanosine 5 triphosphate
    Mutation Research, 2011
    Co-Authors: Mika Hori, Hiroyuki Kamiya, Tetsuya Suzuki, Noriaki Minakawa, Akira Matsuda, Hideyoshi Harashima
    Abstract:

    Abstract 8-Oxo-7,8-dihydroguanine (8-Hydroxyguanine) is oxidized more easily than normal nucleobases, which can produce spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh). These secondary oxidation products of 8-oxo-7,8-dihydroguanine are highly mutagenic when formed within DNA. To evaluate the mutagenicity of the corresponding oxidation products of 8-oxo-7,8-dihydro-2′-deoxyguanosine 5′-triphosphate (8-hydroxy-2′- deoxyguanosine 5′-triphosphate) in the nucleotide pool, Escherichia coli cells deficient in the mutT gene were treated with H2O2, and the induced mutations were analyzed. Moreover, the 2′-deoxyriboside 5′-triphosphate derivatives of Sp and Gh were also introduced into competent E. coli cells. The H2O2 treatment of mutT E. coli cells resulted in increase of G:C → T:A and A:T → T:A mutations. However, the incorporation of exogenous Sp and Gh 2′-deoxyribonucleotides did not significantly increase the mutation frequency. These results suggested that the oxidation product(s) of 8-oxo-7,8-dihydro-2′-deoxyguanosine 5′-triphosphate induces G:C → T:A and A:T → T:A mutations, and that the 2′-deoxyriboside 5′-triphosphate derivatives of Sp and Gh exhibit quite weak mutagenicity, in contrast to the bases in DNA.

  • mutagenic potentials of damaged nucleic acids produced by reactive oxygen nitrogen species approaches using synthetic oligonucleotides and nucleotides survey and summary
    Nucleic Acids Research, 2003
    Co-Authors: Hiroyuki Kamiya
    Abstract:

    DNA and DNA precursors (deoxyribonucleotides) suffer damage by reactive oxygen/nitrogen species. They are important mutagens for organisms, due to their endogenous formation. Damaged DNA and nucleotides cause alterations of the genetic information by the mispairing properties of the damaged bases, such as 8-Hydroxyguanine (7,8-dihydro-8-oxoguanine) and 2-hydroxyadenine. Here, the author reviews the mutagenic potentials of damaged bases in DNA and of damaged DNA precursors formed by reactive oxygen/nitrogen species, focusing on the results obtained with synthetic oligonucleotides and 2'-deoxyribonucleoside 5'-triphosphates.

Miral Dizdaroglu - One of the best experts on this subject based on the ideXlab platform.

  • inhibition by tetrahydroquinoline sulfonamide derivatives of the activity of human 8 oxoguanine dna glycosylase ogg1 for several products of oxidatively induced dna base lesions
    ACS Chemical Biology, 2021
    Co-Authors: Melis Kant, Pawel Jaruga, Stephen R. Lloyd, Yu Ki Tahara, Erdem Coskun, Eric T Kool, Miral Dizdaroglu
    Abstract:

    DNA glycosylases involved in the first step of the DNA base excision repair pathway are promising targets in cancer therapy. There is evidence that reduction of their activities may enhance cell killing in malignant tumors. Recently, two tetrahydroquinoline compounds named SU0268 and SU0383 were reported to inhibit OGG1 for the excision of 8-Hydroxyguanine. This DNA repair protein is one of the major cellular enzymes responsible for excision of a number of oxidatively induced lesions from DNA. In this work, we used gas chromatography-tandem mass spectrometry with isotope-dilution to measure the excision of not only 8-Hydroxyguanine but also that of the other major substrate of OGG1, i.e., 2,6-diamino-4-hydroxy-5-formamidopyrimidine, using genomic DNA with multiple purine- and pyrimidine-derived lesions. The excision of a minor substrate 4,6-diamino-5-formamidopyrimidine was also measured. Both SU0268 and SU0383 efficiently inhibited OGG1 activity for these three lesions, with the former being more potent than the latter. Dependence of inhibition on concentrations of SU0268 and SU0383 from 0.05 μmol/L to 10 μmol/L was also demonstrated. The approach used in this work may be applied to the investigation of OGG1 inhibition by SU0268 and SU0383 and other small molecule inhibitors in further studies including cellular and animal models of disease.

  • Evidence for the Involvement of DNA Repair Enzyme NEIL1 in Nucleotide Excision
    2009
    Co-Authors: Pawel Jaruga, Yan Xiao, Vladimir Vartanian, Stephen R. Lloyd, Miral Dizdaroglu
    Abstract:

    ABSTRACT: The DNA repair enzyme NEIL1 is a DNA glycosylase that is involved in the first step of base excision repair (BER) of oxidatively induced DNA damage. NEIL1 exhibits a strong preference for excision of 4,6-diamino-5-formamidopyrimidine (FapyAde) and 2,6-diamino-4hydroxy-5-formamidopyrimidine (FapyGua) from DNA with no specificity for 8-Hydroxyguanine (8-OH-Gua). In this study, we report on the significant accumulation o

  • Reduced repair of 8-Hydroxyguanine in the human breast cancer cell line, HCC1937
    BMC Cancer, 2006
    Co-Authors: Simon G Nyaga, Pawel Jaruga, Miral Dizdaroglu, Althaf Lohani, Andrzej R Trzeciak, Michele K Evans
    Abstract:

    Background Breast cancer is the second leading cause of cancer deaths in women in the United States. Although the causes of this disease are incompletely understood, oxidative DNA damage is presumed to play a critical role in breast carcinogenesis. A common oxidatively induced DNA lesion is 8-Hydroxyguanine (8-OH-Gua), which has been implicated in carcinogenesis. The aim of this study was to investigate the ability of HCC1937 and MCF-7 breast cancer cell lines to repair 8-OH-Gua relative to a nonmalignant human mammary epithelial cell line, AG11134. Methods We used oligonucleotide incision assay to analyze the ability of the two breast cancer cell lines to incise 8-OH-Gua relative to the control cell line. Liquid chromatography/mass spectrometry (LC/MS) was used to measure the levels of 8-OH-Gua as its nucleoside, 8-OH-dG in the cell lines after exposure to H_2O_2 followed by 30 min repair period. Protein expression levels were determined by Western blot analysis, while the hOGG1 mRNA levels were analyzed by RT-PCR. Complementation of hOGG1 activity in HCC1937 cells was assessed by addition of the purified protein in the incision assay, and in vivo by transfection of pFlagCMV-4- hOGG1 . Clonogenic survival assay was used to determine sensitivity after H_2O_2-mediated oxidative stress. Results We show that the HCC1937 breast cancer cells have diminished ability to incise 8-OH-Gua and they accumulate higher levels of 8-OH-dG in the nuclear genome after H_2O_2 treatment despite a 30 min repair period when compared to the nonmalignant mammary cells. The defective incision of 8-OH-Gua was consistent with expression of undetectable amounts of hOGG1 in HCC1937 cells. The reduced incision activity was significantly stimulated by addition of purified hOGG1. Furthermore, transfection of pFlagCMV-4- hOGG1 in HCC1937 cells resulted in enhanced incision of 8-OH-Gua. HCC1937 cells are more sensitive to high levels of H_2O_2 and have up-regulated SOD1 and SOD2. Conclusion This study provides evidence for inefficient repair of 8-OH-Gua in HCC1937 breast cancer cell line and directly implicates hOGG1 in this defect.

  • primary fibroblasts of cockayne syndrome patients are defective in cellular repair of 8 Hydroxyguanine and 8 hydroxyadenine resulting from oxidative stress
    The FASEB Journal, 2003
    Co-Authors: Jingsheng Tuo, Vilhelm A Bohr, Pawel Jaruga, Henry Rodriguez, Miral Dizdaroglu
    Abstract:

    Cockayne syndrome (CS) is a genetic human disease with clinical symptoms that include neurodegeneration and premature aging. The disease is caused by the disruption of CSA, CSB, or some types of xeroderma pigmentosum genes. It is known that the CSB protein coded by the CS group B gene plays a role in the repair of 8-Hydroxyguanine (8-OH-Gua) in transcription-coupled and non-strand discriminating modes. Recently we reported a defect of CSB mutant cells in the repair of another oxidatively modified lesion 8-hydroxyadenine (8-OH-Ade). We show here that primary fibroblasts from CS patients lack the ability to efficiently repair these particular types of oxidatively induced DNA damages. Primary fibroblasts of 11 CS patients and 6 control individuals were exposed to 2 Gy of ionizing radiation to induce oxidative DNA damage and allowed to repair the damage. DNA from cells was analyzed using liquid chromatography/isotope dilution mass spectrometry to measure the biologically important lesions 8-OH-Gua and 8-OH-Ade. After irradiation, no significant change in background levels of 8-OH-Gua and 8-OH-Ade was observed in control human cells, indicating their complete cellular repair. In contrast, cells from CS patients accumulated significant amounts of these lesions, providing evidence for a lack of DNA repair. This was supported by the observation that incision of 8-OH-Gua- or 8-OH-Ade-containing oligodeoxynucleotides by whole cell extracts of fibroblasts from CS patients was deficient compared to control individuals. This study suggests that the cells from CS patients accumulate oxidatively induced specific DNA base lesions, especially after oxidative stress. A deficiency in cellular repair of oxidative DNA damage might contribute to developmental defects in CS patients.

  • the cockayne syndrome group b gene product is involved in general genome base excision repair of 8 Hydroxyguanine in dna
    Journal of Biological Chemistry, 2001
    Co-Authors: Jingsheng Tuo, Meltem Muftuoglu, Catheryne Chen, Pawel Jaruga, Rebecca R Selzer, Robert M Brosh, Henry Rodriguez, Miral Dizdaroglu, Vilhelm A Bohr
    Abstract:

    Cockayne Syndrome (CS) is a human genetic disorder with two complementation groups, CS-A and CS-B. The CSB gene product is involved in transcription-coupled repair of DNA damage but may participate in other pathways of DNA metabolism. The present study investigated the role of different conserved helicase motifs of CSB in base excision repair. Stably transformed human cell lines with site-directed CSB mutations in different motifs within its putative helicase domain were established. We find that CSB null and helicase motif V and VI mutants had greater sensitivity than wild type cells to gamma-radiation. Whole cell extracts from CSB null and motif V/VI mutants had lower activity of 8-Hydroxyguanine incision in DNA than wild type cells. Also, 8-Hydroxyguanine accumulated more in CSB null and motif VI mutant cells than in wild type cells after exposure to gamma-radiation. We conclude that a deficiency in general genome base excision repair of selective modified DNA base(s) might contribute to CS pathogenesis. Furthermore, whereas the disruption of helicase motifs V or VI results in a CSB phenotype, mutations in other helicase motifs do not cause this effect. The biological functions of CSB in different DNA repair pathways may be mediated by distinct functional motifs of the protein.

Kazuya Shinmura - One of the best experts on this subject based on the ideXlab platform.

  • Impaired 8-Hydroxyguanine Repair Activity of MUTYH Variant p.Arg109Trp Found in a Japanese Patient with Early-Onset Colorectal Cancer
    Hindawi Limited, 2014
    Co-Authors: Kazuya Shinmura, Masanori Goto, Hong Tao, Tomonari Matsuda, Hisami Kato, Rie Suzuki, Satoki Nakamura, Guang Yin, Makiko Morita, Suminori Kono
    Abstract:

    Purpose. The biallelic inactivation of the 8-Hydroxyguanine repair gene MUTYH leads to MUTYH-associated polyposis (MAP), which is characterized by colorectal multiple polyps and carcinoma(s). However, only limited information regarding MAP in the Japanese population is presently available. Since early-onset colorectal cancer (CRC) is a characteristic of MAP and might be caused by the inactivation of another 8-Hydroxyguanine repair gene, OGG1, we investigated whether germline MUTYH and OGG1 mutations are involved in early-onset CRC in Japanese patients. Methods. Thirty-four Japanese patients with early-onset CRC were examined for germline MUTYH and OGG1 mutations using sequencing. Results. Biallelic pathogenic mutations were not found in any of the patients; however, a heterozygous p.Arg19*  MUTYH variant and a heterozygous p.Arg109Trp MUTYH variant were detected in one patient each. The p.Arg19* and p.Arg109Trp corresponded to p.Arg5* and p.Arg81Trp, respectively, in the type 2 nuclear-form protein. The defective DNA repair activity of p.Arg5* is apparent, while that of p.Arg81Trp has been demonstrated using DNA cleavage and supF forward mutation assays. Conclusion. These results suggest that biallelic MUTYH or OGG1 pathogenic mutations are rare in Japanese patients with early-onset CRC; however, the p.Arg19* and p.Arg109Trp MUTYH variants are associated with functional impairments

  • MUTATION IN BRIEF HUMAN MUTATION Adenine DNA Glycosylase Activity of 14 Human MutY Homolog (MUTYH) Variant Proteins Found in Patients with Colorectal Polyposis and Cancer OFFICIAL JOURNAL www.hgvs.org
    2013
    Co-Authors: Masanori Goto, Kazuya Shinmura, Hong Tao, Hidetaka Yamada, Haruhiko Sugimura, Toshihiro Tsuneyoshi, Communicated Riccardo Fodde
    Abstract:

    ABSTRACT: Biallelic inactivating germline mutations in the base excision repair MUTYH (MYH) gene have been shown to predispose to MUTYH-associated polyposis (MAP), which is characterized by multiple colorectal adenomas and carcinomas. In this study, we successfully prepared highly homogeneous human MUTYH type 2 recombinant proteins and compared the DNA glycosylase activity of the wild-type protein and fourteen variant-type proteins on adenine mispaired with 8-Hydroxyguanine, an oxidized form of guanine. The adenine DNA glycosylase activity of the p.I195V protein, p.G368D protein, p.M255V protein, and p.Y151C protein was 66.9%, 15.2%, 10.7%, and 4.5%, respectively, of that of the wild-type protein, and the glycosylase activity of the p.R154H, p.L360P, p.P377L, p.452delE, p.R69X, and p.Q310X proteins as well as of the p.D208N negative control form was extremely severely impaired. The glycosylase activity of the p.V47E, p.R281C, p.A345V, and p.S487F proteins, on the other hand, was almost the same as that of the wild-type protein. These results should be of great value in accurately diagnosing MAP and in fully understanding the mechanism by which MUTYH repairs DNA in which adenine is mispaired wit

  • reduced expression of mutyh with suppressive activity against mutations caused by 8 Hydroxyguanine is a novel predictor of a poor prognosis in human gastric cancer
    The Journal of Pathology, 2011
    Co-Authors: Kazuya Shinmura, Masanori Goto, Hong Tao, Shun Matsuura, Masaya Suzuki, Hidetaka Yamada, Hisaki Igarashi, Matsuyoshi Maeda, Hiroyuki Konno, Tomonari Matsuda
    Abstract:

    The MUTYH gene encodes a DNA glycosylase that can initiate the excision repair of adenine mispaired with 8-Hydroxyguanine (8OHG) and is responsible for a susceptibility to multiple colorectal adenomas and carcinomas. To determine whether the MUTYH gene is involved in gastric carcinogenesis, we first examined the expression level of MUTYH in gastric cancer. The reduced expression of MUTYH mRNA transcript was detected in both gastric cancer cell lines and primary gastric cancers using qRT–PCR analysis. Immunohistochemical analysis also showed a significant reduction in MUTYH protein expression in gastric cancer, compared with non-cancerous gastric epithelium (immunohistochemical score, 175.5 ± 43.0 versus 281.5 ± 24.8; p < 0.0001). Among the gastric cancers, the MUTYH expression level was significantly associated with the histopathology (p < 0.0001) and the pT stage (p < 0.001). The outcome of patients with gastric cancer exhibiting low MUTYH expression was significantly worse than the outcome of patients with gastric cancer exhibiting high MUTYH expression (p = 0.0007, log-rank test) and a multivariate analysis revealed that reduced MUTYH expression was an independent predictor of a poor survival outcome among the gastric cancer patients (hazard ratio, 1.865; 95% confidence interval, 1.028–3.529; p = 0.0401). We next compared the functional effects of MUTYH on gastric cancer cells, based on their MUTYH expression levels. MUTYH-over-expressing stable clones of the gastric cancer cell line AGS showed: (a) higher DNA cleavage activity towards adenine:8OHG mispair-containing substrates; (b) higher suppressive activity against mutations caused by 8OHG in a supF forward mutation assay; and (c) higher suppressive activity for cellular proliferation than empty vector-transfected AGS clones. These results suggested that MUTYH is a suppressor of mutations caused by 8OHG in gastric cells and that its reduced expression is associated with a poor prognosis in gastric cancer. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • adenine dna glycosylase activity of 14 human muty homolog mutyh variant proteins found in patients with colorectal polyposis and cancer
    Human Mutation, 2010
    Co-Authors: Masanori Goto, Kazuya Shinmura, Hong Tao, Hidetaka Yamada, Yusaku Nakabeppu, Toshihiro Tsuneyoshi, Haruhiko Sugimura
    Abstract:

    Biallelic inactivating germline mutations in the base excision repair MUTYH (MYH) gene have been shown to predispose to MUTYH-associated polyposis (MAP), which is characterized by multiple colorectal adenomas and carcinomas. In this study, we successfully prepared highly homogeneous human MUTYH type 2 recombinant proteins and compared the DNA glycosylase activity of the wild-type protein and fourteen variant-type proteins on adenine mispaired with 8-Hydroxyguanine, an oxidized form of guanine. The adenine DNA glycosylase activity of the p.I195V protein, p.G368D protein, p.M255V protein, and p.Y151C protein was 66.9%, 15.2%, 10.7%, and 4.5%, respectively, of that of the wild-type protein, and the glycosylase activity of the p.R154H, p.L360P, p.P377L, p.452delE, p.R69X, and p.Q310X proteins as well as of the p.D208N negative control form was extremely severely impaired. The glycosylase activity of the p.V47E, p.R281C, p.A345V, and p.S487F proteins, on the other hand, was almost the same as that of the wild-type protein. These results should be of great value in accurately diagnosing MAP and in fully understanding the mechanism by which MUTYH repairs DNA in which adenine is mispaired with 8-Hydroxyguanine. © 2010 Wiley-Liss, Inc.

  • the ogg1 gene encodes a repair enzyme for oxidatively damaged dna and is involved in human carcinogenesis
    Antioxidants & Redox Signaling, 2001
    Co-Authors: Kazuya Shinmura, Jun Yokota
    Abstract:

    8-Hydroxyguanine (oh8G) is a major base lesion produced by reactive oxygen species. oh8G in DNA causes G:C to T:A transversions and, thus, could be responsible for mutations that lead to carcinogenesis. A human DNA glycosylase/AP lyase encoded by the OGG1 gene has an activity to remove directly oh8G from DNA, and suppresses the mutagenic effect of oh8G. OGG1 protein has a helix-hairpin-helix-GPD motif as a domain for both DNA binding and catalysis, a nuclear localization signal, and a mitochondria targeting signal. Among multiple OGG1 isoforms, OGG1-type la is expressed predominantly in human cells and repairs chromosomal DNA in the nucleus. Inactivation of the OGG1 gene in yeast and mice leads to elevated spontaneous mutation frequency in the cells. The human OGG1 gene maps to chromosome 3p26.2, and allelic deletions of this region occur frequently in a variety of human cancers. Moreover, the OGG1 gene is somatically mutated in some cancer cells and is highly polymorphic among human populations. Repair activities of some mutated and polymorphic OGG1 proteins are lower than those of wild-type OGG1-type la-Ser326 protein and, thus, could be involved in human carcinogenesis.

Haruhiko Sugimura - One of the best experts on this subject based on the ideXlab platform.

  • Research Article Impaired 8-Hydroxyguanine Repair Activity of MUTYH Variant p.Arg109Trp Found in a Japanese Patient with Early-Onset Colorectal Cancer
    2016
    Co-Authors: Suminori Kono, Haruhiko Sugimura
    Abstract:

    Copyright © 2014 Kazuya Shinmura et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose. The biallelic inactivation of the 8-Hydroxyguanine repair gene MUTYH leads to MUTYH-associated polyposis (MAP), which is characterized by colorectal multiple polyps and carcinoma(s). However, only limited information regarding MAP in the Japanese population is presently available. Since early-onset colorectal cancer (CRC) is a characteristic of MAP and might be caused by the inactivation of another 8-Hydroxyguanine repair gene, OGG1, we investigated whether germline MUTYH and OGG1 mutations are involved in early-onset CRC in Japanese patients. Methods. Thirty-four Japanese patients with early-onset CRC were examined for germline MUTYH and OGG1 mutations using sequencing. Results. Biallelic pathogenic mutations were not found in any of the patients; however, a heterozygous p.Arg19 ∗ MUTYH variant and a heterozygous p.Arg109Trp MUTYH variant were detected in one patient each. The p.Arg19 ∗ and p.Arg109Trp corresponded to p.Arg5 ∗ and p.Arg81Trp, respectively, in the type 2 nuclear-form protein. The defective DNA repair activity of p.Arg5 ∗ is apparent, while that of p.Arg81Trp has been demonstrated using DNA cleavage and supF forward mutation assays. Conclusion.These results suggest that biallelic MUTYH o

  • MUTATION IN BRIEF HUMAN MUTATION Adenine DNA Glycosylase Activity of 14 Human MutY Homolog (MUTYH) Variant Proteins Found in Patients with Colorectal Polyposis and Cancer OFFICIAL JOURNAL www.hgvs.org
    2013
    Co-Authors: Masanori Goto, Kazuya Shinmura, Hong Tao, Hidetaka Yamada, Haruhiko Sugimura, Toshihiro Tsuneyoshi, Communicated Riccardo Fodde
    Abstract:

    ABSTRACT: Biallelic inactivating germline mutations in the base excision repair MUTYH (MYH) gene have been shown to predispose to MUTYH-associated polyposis (MAP), which is characterized by multiple colorectal adenomas and carcinomas. In this study, we successfully prepared highly homogeneous human MUTYH type 2 recombinant proteins and compared the DNA glycosylase activity of the wild-type protein and fourteen variant-type proteins on adenine mispaired with 8-Hydroxyguanine, an oxidized form of guanine. The adenine DNA glycosylase activity of the p.I195V protein, p.G368D protein, p.M255V protein, and p.Y151C protein was 66.9%, 15.2%, 10.7%, and 4.5%, respectively, of that of the wild-type protein, and the glycosylase activity of the p.R154H, p.L360P, p.P377L, p.452delE, p.R69X, and p.Q310X proteins as well as of the p.D208N negative control form was extremely severely impaired. The glycosylase activity of the p.V47E, p.R281C, p.A345V, and p.S487F proteins, on the other hand, was almost the same as that of the wild-type protein. These results should be of great value in accurately diagnosing MAP and in fully understanding the mechanism by which MUTYH repairs DNA in which adenine is mispaired wit

  • adenine dna glycosylase activity of 14 human muty homolog mutyh variant proteins found in patients with colorectal polyposis and cancer
    Human Mutation, 2010
    Co-Authors: Masanori Goto, Kazuya Shinmura, Hong Tao, Hidetaka Yamada, Yusaku Nakabeppu, Toshihiro Tsuneyoshi, Haruhiko Sugimura
    Abstract:

    Biallelic inactivating germline mutations in the base excision repair MUTYH (MYH) gene have been shown to predispose to MUTYH-associated polyposis (MAP), which is characterized by multiple colorectal adenomas and carcinomas. In this study, we successfully prepared highly homogeneous human MUTYH type 2 recombinant proteins and compared the DNA glycosylase activity of the wild-type protein and fourteen variant-type proteins on adenine mispaired with 8-Hydroxyguanine, an oxidized form of guanine. The adenine DNA glycosylase activity of the p.I195V protein, p.G368D protein, p.M255V protein, and p.Y151C protein was 66.9%, 15.2%, 10.7%, and 4.5%, respectively, of that of the wild-type protein, and the glycosylase activity of the p.R154H, p.L360P, p.P377L, p.452delE, p.R69X, and p.Q310X proteins as well as of the p.D208N negative control form was extremely severely impaired. The glycosylase activity of the p.V47E, p.R281C, p.A345V, and p.S487F proteins, on the other hand, was almost the same as that of the wild-type protein. These results should be of great value in accurately diagnosing MAP and in fully understanding the mechanism by which MUTYH repairs DNA in which adenine is mispaired with 8-Hydroxyguanine. © 2010 Wiley-Liss, Inc.

  • genetic polymorphisms and alternative splicing of the hogg1 gene that is involved in the repair of 8 Hydroxyguanine in damaged dna
    Oncogene, 1998
    Co-Authors: Takashi Kohno, Hiroshi Kasai, Kazuya Shinmura, Haruhiko Sugimura, Masahiko Tosaka, Masachika Tani, Suryang Kim, Takehiko Nohmi, Jun Yokota
    Abstract:

    The hOGG1 gene encodes a DNA glycosylase that excises 8-Hydroxyguanine (oh8Gua) from damaged DNA. Structural analyses of the hOGG1 gene and its transcripts were performed in normal and lung cancer cells. Due to a genetic polymorphism at codon 326, hOGG1-Ser326 and hOGG1-Cys326 proteins were produced in human cells. Activity in the repair of oh8Gua was greater in hOGG1-Ser326 protein than in hOGG1-Cys326 protein in the complementation assay of an E. coli mutant defective in the repair of oh8Gua. Two isoforms of hOGG1 transcripts produced by alternative splicing encoded distinct hOGG1 proteins: one with and the other without a putative nuclear localization signal. Loss of heterozygosity at the hOGG1 locus was frequently (15/ 23, 62.2%) detected in lung cancer cells, and a cell line NCI-H526 had a mutation leading to the formation of the transcripts encoding a truncated hOGG1 protein. However, the oh8Gua levels in nuclear DNA were similar among lung cancer cells and leukocytes irrespective of the type of hOGG1 proteins expressed. These results suggest that the oh8Gua levels are maintained at a steady level, even though multiple hOGG1 proteins are produced due to genetic polymorphisms, mutations and alternative splicing of the hOGG1 gene.