The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Leona D Samson - One of the best experts on this subject based on the ideXlab platform.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced Chromosome Damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, A Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:Abstract In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced Chromosome Damage, and to cell killing induced by two methylating agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced Chromosome Damage and cytotoxicity.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced Chromosome Damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, A Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced Chromosome Damage, and to cell killing induced by two methylating agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced Chromosome Damage and cytotoxicity.
H. C. Andersson - One of the best experts on this subject based on the ideXlab platform.
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Enhancement and reduction by methylated oxypurines of the frequencies of chromatid aberrations induced by camptothecin in root-tip cells of Vicia faba
Mutation Research, 1992Co-Authors: B. A. Kihlman, H. C. AnderssonAbstract:Abstract In root-tip cells of Vicia faba the frequencies of chromatid aberrations induced by 3-h treatments with 0.05 μM camptothecin were strongly modified when the treatments were carried out in the presence of caffeine at concentrations above 1 mM. Depending in the concentration of caffeine, the clastogenic effect of camptothecin was either enhanced or reduced. At concentrations between 1 and 6 mM, caffeine increased the camptothecin-induced Chromosome Damage, the strongest enhancement being obtained at 5 mM. A reduction of the Chromosome Damage was apparent at caffeine concentrations above 10 mM, and in the presence of 20 mM caffeine the clastogenic effect of camptothecin was almost completely suppressed. When present during the camptothecin treatment, theophylline, 8-chlorocaffeine and 1,3,7,9-tetramethyluric acid influenced the induced Chromosome Damage in a similar way as caffeine, although with varying efficiency. If the concentrations required to produce the two types of modifying effect are used as a criterion, 8-chlorocaffeine was the most effective and 1,3,7,9-tetramethyluric acid the least, whereas caffeine and theophylline were about equally effective.
Bevin P Engelward - One of the best experts on this subject based on the ideXlab platform.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced Chromosome Damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, A Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:Abstract In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced Chromosome Damage, and to cell killing induced by two methylating agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced Chromosome Damage and cytotoxicity.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced Chromosome Damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, A Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced Chromosome Damage, and to cell killing induced by two methylating agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced Chromosome Damage and cytotoxicity.
Patrick Sung - One of the best experts on this subject based on the ideXlab platform.
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mechanism and significance of Chromosome Damage repair by homologous recombination
Essays in Biochemistry, 2020Co-Authors: Ajinkya S Kawale, Patrick SungAbstract:Homologous recombination (HR) is a major, conserved pathway of Chromosome Damage repair. It not only fulfills key functions in the removal of deleterious lesions such as DNA double-strand breaks (DSBs) and interstrand cross-links (ICLs), but also in replication fork repair and protection. Several familial and acquired cancer predisposition syndromes stem from defects in HR. In particular, individuals with mutations in HR genes exhibit predisposition to breast, ovarian, pancreatic, and prostate cancers, and they also show signs of accelerated aging. However, aberrant and untimely HR events can lead to the loss of heterozygosity, genomic rearrangements, and cytotoxic nucleoprotein intermediates. Thus, it is critically important that HR be tightly regulated. In addition to DNA repair, HR is also involved in meiotic Chromosome segregation and telomere maintenance in cells that lack telomerase. In this review, we focus on the role of HR in DSB repair (DSBR) and summarize the current state of the field.
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the brca tumor suppressor network in Chromosome Damage repair by homologous recombination
Annual Review of Biochemistry, 2019Co-Authors: Patrick Sung, Weixing Zhao, Claudia Wiese, Youngho Kwon, Robert HromasAbstract:Mutations in the BRCA1 and BRCA2 genes predispose afflicted individuals to breast, ovarian, and other cancers. The BRCA-encoded products form complexes with other tumor suppressor proteins and with the recombinase enzyme RAD51 to mediate Chromosome Damage repair by homologous recombination and also to protect stressed DNA replication forks against spurious nucleolytic attrition. Understanding how the BRCA tumor suppressor network executes its biological functions would provide the foundation for developing targeted cancer therapeutics, but progress in this area has been greatly hampered by the challenge of obtaining purified BRCA complexes for mechanistic studies. In this article, we review how recent effort begins to overcome this technical challenge, leading to functional and structural insights into the biochemical attributes of these complexes and the multifaceted roles that they fulfill in genome maintenance. We also highlight the major mechanistic questions that remain.
Huan Guo - One of the best experts on this subject based on the ideXlab platform.
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multiple metals exposure and Chromosome Damage exploring the mediation effects of micrornas and their potentials in lung carcinogenesis
Environment International, 2019Co-Authors: Weilin Chen, Yansen Bai, Qifei Deng, Xiaomin Zhang, Ke Wang, Gege Wang, Jiao Huang, Sheng Wei, Huan GuoAbstract:Abstract Objective This study aimed to investigate the associations of multiple metals with Chromosome Damage, and further explore the mediation roles of microRNAs (miRNAs) and their potentials in lung cancer. Methods We determined the urinary levels of 23 metals, lymphocytic micronucleus (MN) frequency, and ten candidate miRNAs in plasma among 365 healthy workers. Poisson and linear regression models were conducted to analyze the associations of urinary metals with MN frequency and miRNAs, respectively. The mediation effects of miRNAs on the metal-MN frequency associations were assessed by causal mediation analysis. Additionally, the levels of effective metal and miRNAs were measured in 43 pair-wised tumor and normal lung tissues. Results The urinary level of titanium was inversely associated with MN frequency after Bonferroni correction [frequency ratio (FR) and 95% confidence interval (95%CI) = 0.88 (0.82, 0.94), p = 5.0 × 10−4]. A doubling in urinary titanium was associated with 14.72%–38.17% decrease in plasma miRNAs. After multiple comparison, miR-24-3p and miR-28-5p significantly mediated 24.8% (7.7%, 70.0%) and 20.4% (5.7%, 52.0%) of the association between titanium and MN frequency (pmediation = 0.002 and 0.004, respectively). Besides, a doubling in titanium was associated with a separate 53.4% and 47.2% decreased miR-24-3p and miR-28-5p expression in normal lung tissues. Lower titanium but higher levels of miR-24-3p and miR-28-5p were shown in tumor than normal tissues of lung squamous cell carcinoma patients (all p Conclusions Our study proposed the negative associations of titanium with Chromosome Damage and lung cancer, and highlighted the mediating roles of miR-24-3p and miR-28-5p. Further investigations are warranted to validate these associations and uncover the underlying mechanisms.
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essential metals zinc selenium and strontium protect against Chromosome Damage caused by polycyclic aromatic hydrocarbons exposure
Environmental Science & Technology, 2016Co-Authors: Yansen Bai, Suhan Wang, Xiao Zhang, Wangzhen Zhang, Xiaomin Zhang, Wei Feng, Huan GuoAbstract:Essential metals play important roles in maintaining cellular homeostasis, but the effects of their interaction with the environmental pollutants are still not very well-known in human subjects. The aim of this study was to evaluate the roles of essential metals and their interactions with polycyclic aromatic hydrocarbons (PAHs) on Chromosome Damage, an early carcinogenic event. A total of 1245 male workers were included in this study and the levels of 11 urinary essential metals, 12 urinary PAH metabolites, plasma concentrations of benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, and lymphocyte micronucleus (MN) frequencies were monitored. We found that zinc (Zn), selenium (Se), and strontium (Sr) have significant inverse dose-response relationships with MN frequencies (all P < 0.05). Furthermore, the protective roles of Zn, Se, and Sr were mainly shown among subjects with high levels of BPDE-Alb adducts. Significant effect modification of BPDE-Alb adducts on the associations of Zn, Se, and Sr with MN frequencies was observed (all Pinteraction < 0.05). Our study showed evidence that Zn, Se, and Sr play protective roles in reducing Chromosome Damage, and these effects can be modified by PAH exposure levels. These findings add potential evidence for the preventive effects of Zn, Se, and Sr against carcinogenesis in human subjects.
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the interaction of apex1 variant with polycyclic aromatic hydrocarbons on increasing Chromosome Damage and lung cancer risk among male chinese
Molecular Carcinogenesis, 2015Co-Authors: Jinyu Wei, Xiao Zhang, Tian Wang, Xiaomin Zhang, Xiangqian Yin, Li Liu, Kai Zhang, Changchun Zhou, Ming Yang, Huan GuoAbstract:Polycyclic aromatic hydrocarbons (PAHs) are the most significant contributors to tobacco-induced lung carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central enzyme in the removal of apurinic/apyrimidinic sites caused by DNA damaging agents. This study aimed to investigate the potential interaction of APEX1 polymorphisms and PAHs on genetic Damage and lung cancer risk among male Chinese. We recruited an occupational cohort of 922 male coke oven workers and determined their DNA Damage levels by calculating the lymphocytic micronucleus (MN) frequencies. Two well-studied APEX1 polymorphisms (−307A > C and Asp148Glu) and their associations with MN frequencies were examined. The impact of MN-related single nucleotide polymorphism (SNP) on lung cancer risk was further investigated in two case-control studies including 1634 male lung cancer patients and 1678 controls. It was shown that, the APEX1 148Glu allele was associated with significantly higher MN frequencies than 148Asp allele, with strongest associations among the highest PAH-exposure workers (P = 0.008). The APEX1 148Glu allele was also associated with increased lung cancer risk among male smokers, especially among heavy smokers in both case-control studies (odd ratio: 4.40, 95%CI: 3.29–5.72). In addition, APEX1 148Glu variant interacts with smoking in increasing male lung cancer risk, as measured by the attributable proportion due to interaction, which was 0.23 (95%CI: 0.06–0.39). This study showed evidence on interaction between APEX1 148Glu variant and cigarette smoking in increasing lung cancer susceptibility among male Chinese, which may be due to the synergistic effects of APEX1 148Glu and PAHs in increasing Chromosome Damage levels. The results provide a new insight into gene-interactions in lung carcinogenesis. © 2014 Wiley Periodicals, Inc.
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association of body mass index with Chromosome Damage levels and lung cancer risk among males
Scientific Reports, 2015Co-Authors: Yansen Bai, Suhan Wang, Samuel Mwangi Nyamathira, Xiao Zhang, Wangzhen Zhang, Tian Wang, Qifei Deng, Xiaomin Zhang, Huan GuoAbstract:Epidemiological studies have shown an etiological link between body mass index (BMI) and cancer risk, but evidence supporting these observations is limited. This study aimed to investigate potential associations of BMI with Chromosome Damage levels and lung cancer risk. First, we recruited 1333 male workers from a coke-oven plant to examine their Chromosome Damage levels; and then, a cohort study of 12 052 males was used to investigate the association of BMI with lung cancer incidence. We further carried out a meta-analysis for BMI and male lung cancer risk based on cohort studies. We found that men workers with excess body weight (BMI ≥ 25 kg/m2) had lower levels of MN frequencies than men with normal-weight (BMI: 18.5–24.9). Our cohort study indicated that, the relative risk (RR) for men with BMI ≥ 25 to develop lung cancer was 35% lower than RR for normal-weight men. Further meta-analysis showed that, compared to normal-weight men, men with BMI ≥ 25 had decreased risk of lung cancer among both the East-Asians and others populations. These results indicate that men with excess body weight had significant decreased Chromosome Damage levels and lower risk of lung cancer than those with normal-weight. However, further biological researches were needed to validate these associations.
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women are more susceptible than men to oxidative stress and Chromosome Damage caused by polycyclic aromatic hydrocarbons exposure
Environmental and Molecular Mutagenesis, 2014Co-Authors: Huan Guo, Xiao Zhang, Wangzhen Zhang, Qifei Deng, Xiaomin Zhang, Kun Huang, Lei Guan, Dan Kuang, Huaxin Deng, David C ChristianiAbstract:Exposure to environmental polycyclic aromatic hydrocarbons (PAHs) has been associated with increased risk of cancer, but evidence for gender differences in this association is limited. The aim of this study was to examine the gender differences in PAHs caused early genotoxic effects such as oxidative stress and Chromosome Damage, which are potential carcinogenic etiology of PAHs. A total of 478 nonsmoking workers (272 men and 206 women) from a coke oven plant were recruited. We determined 16 environmental PAHs in their workplaces, and measured concentrations of 12 urinary PAH metabolites (OH-PAHs), plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, urinary 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α), and micronucleus frequencies in lymphocytes in all subjects. It showed that, women working at the office, adjacent to the coke oven, and on the bottom or side of the coke oven displayed significantly higher levels of urinary 8-OHdG and 8-iso-PGF2α, and lymphocytic micronucleus frequencies compared with men working at above areas, respectively (all P < 0.05). These gender differences remain significant after adjusted for potential confounders and urinary ΣOH-PAHs or plasma BPDE-Alb adducts. A significant interaction existed between gender and BPDE-Alb adducts on increasing micronucleus frequencies (Pinteraction < 0.001). We further stratified all workers by the tertiles of urinary ΣOH-PAHs or plasma BPDE-Alb adducts, and the above gender differences were more evident in the median- and high-exposure groups (all P < 0.05). In conclusion, women were more susceptible than men to oxidative stress and Chromosome Damage induced by PAHs, which may add potential evidence underlying gender differences in PAH exposure-related lung cacinogenesis. Environ. Mol. Mutagen. 55:472–481, 2014. © 2014 Wiley Periodicals, Inc.