Polymorphisms of the AS3MT gene are associated with arsenic methylation capacity and damage to the P21 gene in arsenic trioxide plant workers

2021 ◽  
pp. 074823372110133
Author(s):  
Guanghui Ni ◽  
Jingwen Tan ◽  
Mengjie Wang ◽  
Nina Ping ◽  
Min Liu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Arsenic Trioxide ◽  
Kinase Inhibitor ◽  
Quantitative Polymerase Chain Reaction ◽  
Metabolic Efficiency ◽  
Strong Positive Correlation ◽  
Nucleotide Polymorphisms ◽  
Methylation Index ◽  
Methylation Capacity ◽  
Risk Of Cancer

Epidemiological evidence suggests that the metabolic profiles of each individual exposed to arsenic (As) are related to the risk of cancer, coronary heart disease, and diabetes. The arsenite methyltransferase ( AS3MT) gene plays a key role in As metabolism. Several single nucleotide polymorphisms in the AS3MT gene may affect both enzyme activity and gene transcription. AS3MT polymorphisms are associated with the proportions of monomethylarsenic acid (MMA) and dimethylarsenic acid (DMA) in urine as well as the incidence of cancer. P21 protein is a cyclin-dependent kinase inhibitor. Mutations of the P21 gene have been found in cancer patients. In our study, we investigate whether polymorphisms of the AS3MT gene alter As methylation capacity and adversely affect the P21 gene in arsenic trioxide plant workers. The DNA damage was examined by the quantitative polymerase chain reaction. Restriction fragment length polymorphism was used to analyze the genotype of the AS3MT gene. The results showed that DNA damage in P21 gene fragments was greater in those individuals exposed to high levels of As. There was a strong positive correlation between the DNA damage to P21 gene fragments and the percentage of MMA in urine. However, DNA damage in P21 gene fragments was negatively associated with the percentage of DMA in urine (%uDMA), primary methylation index (PMI), and secondary methylation index. We found that subjects with the rs7085104 GG or GA allele were associated with higher %uDMA and PMI and less DNA damage. The subjects with the rs11191454 GG+GA or GA allele were also associated with higher %uDMA and PMI and less DNA damage. Our results suggest that rs1191454 and rs7085104 in the AS3MT gene affect the As-induced DNA damage by altering individual metabolic efficiency.

The ability of arsenic metabolism affected the expression of lncRNA PANDAR, DNA damage, or DNA methylation in peripheral blood lymphocytes of laborers

2019 ◽  
Vol 39 (5) ◽  
pp. 605-613 ◽  
Author(s):  
Y He ◽  
R Zhang ◽  
J Chen ◽  
J Tan ◽  
M Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Damage ◽  
Peripheral Blood ◽  
Quantitative Polymerase Chain Reaction ◽  
Peripheral Blood Lymphocytes ◽  
Dimethylarsinic Acid ◽  
Arsenic Metabolism ◽  
Blood Lymphocytes ◽  
Methylation Index

Arsenic has been associated with significant effects on human health. Exposure to inorganic arsenic has been associated with the changes in gene expression. Promoter of CDKN1A antisense DNA damage activated RNA (PANDAR) expression is induced by p53 protein and DNA damage response. Here, we investigated whether the ability of arsenic metabolism in individuals affected the expression of PANDAR, DNA damage, and DNA methylation. Levels of gene expression and DNA damage were examined by the quantitative polymerase chain reaction and DNA methylation was measured by the methylation-sensitive high-resolution melting curve. In our study, we demonstrated that arsenic exposure increased PANDAR expression and DNA damage among arsenic smelting plant laborers. The PANDAR expression and DNA damage were positively linked to monomethylarsonic acid % ( R = 0.25, p < 0.05 and R = 0.32, p < 0.01) and negatively linked to dimethylarsinic acid % ( R = −0.21, p < 0.05 and R = −0.31, p < 0.01). Subjects with low primary methylation index had increased levels of DNA damage (51.62 ± 2.96 vs. 60.93 ± 3.10, p < 0.05) and methylation (17.14 (15.88–18.51) vs. 15.83 (14.82–18.00), p < 0.05). Subjects with low secondary methylation index had increased levels of PANDAR expression (4.88 ± 0.29 vs. 4.07 ± 0.23, p < 0.01) and DNA damage (17.38 (15.88–19.29) vs. 15.83 (14.82–17.26), p < 0.01). DNA methylation of PANDAR gene was linked to the regulation of its expression in peripheral blood lymphocytes among laborers ( Y = −2.08 × X + 5.64, p < 0.05). These findings suggested arsenic metabolism ability and exposure affected the expression of PANDAR, DNA damage, and DNA methylation.

scholarly journals Exposure of the cytoplasm to low-dose X-rays modifies ataxia telangiectasia mutated-mediated DNA damage responses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Munetoshi Maeda ◽  
Masanori Tomita ◽  
Mika Maeda ◽  
Hideki Matsumoto ◽  
Noriko Usami ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Ataxia Telangiectasia ◽  
Kinase Inhibitor ◽  
Surrogate Marker ◽  
X Rays ◽  
Ataxia Telangiectasia Mutated ◽  
Whole Cell ◽  
X Ray ◽  
Dna Damage Responses

AbstractWe recently showed that when a low X-ray dose is used, cell death is enhanced in nucleus-irradiated compared with whole-cell-irradiated cells; however, the role of the cytoplasm remains unclear. Here, we show changes in the DNA damage responses with or without X-ray microbeam irradiation of the cytoplasm. Phosphorylated histone H2AX foci, a surrogate marker for DNA double-strand breaks, in V79 and WI-38 cells are not observed in nucleus irradiations at ≤ 2 Gy, whereas they are observed in whole-cell irradiations. Addition of an ataxia telangiectasia mutated (ATM) kinase inhibitor to whole-cell irradiations suppresses foci formation at ≤ 2 Gy. ABL1 and p73 expression is upregulated following nucleus irradiation, suggesting the induction of p73-dependent cell death. Furthermore, CDKN1A (p21) is upregulated following whole-cell irradiation, indicating the induction of cell cycle arrest. These data reveal that cytoplasmic radioresponses modify ATM-mediated DNA damage responses and determine the fate of cells irradiated at low doses.

scholarly journals Importance of monitoring arsenic methylation metabolism in acute promyelocytic leukemia patients receiving the treatment of arsenic trioxide

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yu Zheng ◽  
Yuan-Fei Mao ◽  
Hui-Jin Zhao ◽  
Li Chen ◽  
Li-Ning Wang ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Arsenic Speciation ◽  
Promyelocytic Leukemia ◽  
Chronic Liver ◽  
Dimethylarsinic Acid ◽  
Metabolic Pattern ◽  
Methylation Index ◽  
Arsenic Methylation

Abstract Background Arsenic trioxide [ATO, inorganic arsenite (iAsIII) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL). However, the long-term adverse effects (AEs) and the retention of arsenic among APL patients are rarely reported. In this study, we focused on arsenic methylation metabolism and its relationship with chronic hepatic toxicity, as we previously reported, among APL patients who had finished the treatment of ATO. Methods A total of 112 de novo APL patients who had completed the ATO-containing treatment were enrolled in the study. Arsenic species [iAsIII, inorganic arsenate (iAsV), and their organic metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] in patients’ plasma, urine, hair and nails were detected by high-performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Eighteen single nucleotide polymorphisms (SNPs) of the arsenic (+ 3 oxidative state) methylation transferase (AS3MT) gene, which was known as the main catalyzer for arsenic methylation, were tested with the polymerase chain reaction method. Results The study showed the metabolic pattern of arsenic in APL patients undergoing and after the treatment of ATO, in terms of total arsenic (TAs) and four species of arsenic. TAs decreased to normal after 6 months since cessation of ATO. But the arsenic speciation demonstrated significantly higher portion of iAsIII in patient’s urine (40.08% vs. 1.94%, P < 0.001), hair (29.25% vs. 13.29%, P = 0.002) and nails (30.21% vs. 13.64%, P = 0.003) than the healthy controls’, indicating a decreased capacity of arsenic methylation metabolism after the treatment of ATO. Urine primary methylation index (PMI) was significantly lower in patients with both chronic liver dysfunction (0.14 vs. 0.28, P = 0.047) and hepatic steatosis (0.19 vs. 0.3, P = 0.027), suggesting that insufficient methylation of arsenic might be related to chronic liver disorders. Two SNPs (A9749G and A27215G) of the AS3MT gene were associated with impaired urine secondary methylation index (SMI). Conclusions The long-term follow-up of arsenic speciation indicated a decreased arsenic methylation metabolism and a probable relationship with chronic hepatic disorders among APL patients after the cessation of ATO. Urine PMI could be a monitoring index for chronic AEs of ATO, and the SNPs of AS3MT gene should be considered when determining the dosage of ATO.

scholarly journals Involvement of CGRP receptor RAMP1 in cluster headache: A Swedish case-control study

2019 ◽  
Vol 2 ◽  
pp. 251581631987988 ◽  
Author(s):  
Julia M Michalska ◽  
Caroline Ran ◽  
Carmen Fourier ◽  
Anna Steinberg ◽  
Christina Sjöstrand ◽  
...  
Keyword(s):  
Cluster Headache ◽  
Mrna Expression ◽  
Quantitative Polymerase Chain Reaction ◽  
Active Phase ◽  
Nucleotide Polymorphisms ◽  
Cgrp Receptor ◽  
Receptor Component ◽  
Significant Difference ◽  
Potent Vasodilator ◽  
Primary Fibroblasts

Background: Increased levels of the potent vasodilator calcitonin gene-related peptide (CGRP) have been found in ipsilateral jugular vein blood during the active phase of cluster headache (CH) and this is hypothesized to cause distinctive vasodilation. The receptor activity-modifying protein 1 (RAMP1) is part of the CGRP receptor complex responsible for ligand binding and specificity and therefore constitutes a promising candidate gene for CH. The aim of this study was to investigate the possible genetic association of RAMP1 with CH in Sweden, with focus on two RAMP1 single nucleotide polymorphisms, rs3754701 and rs7590387, and quantify RAMP1 mRNA expression levels in biological tissue from CH patients and controls. Methods: rs3754701 and rs7590387 were genotyped by quantitative polymerase chain reaction (qPCR) in 542 CH patients and 585 control subjects. RAMP1 mRNA expression was determined by reverse transcription qPCR in tissue from 12 CH patients and 12 controls. Results: We identified a significant difference between the CH patient and control groups for rs3754701 ( p = 0.0088). In addition, RAMP1 mRNA expression was enhanced in primary fibroblasts from CH patients compared to controls ( p = 0.0073). Conclusion: The association between rs3754701 and CH and the enhanced RAMP1 mRNA expression in CH patients support the hypothesis that CGRP and its receptor component RAMP1 are involved in CH pathophysiology.

scholarly journals Analysis of Symptom Development in Relation to Quantity of Rice stripe virus in Rice (Oryza sativa) to Simplify Evaluation of Resistance

2019 ◽  
Vol 109 (4) ◽  
pp. 701-707 ◽  
Author(s):  
Mitsuru Okuda ◽  
Takuya Shiba ◽  
Masahiro Hirae ◽  
Akira Masunaka ◽  
Minoru Takeshita
Keyword(s):  
Oryza Sativa ◽  
Quantitative Polymerase Chain Reaction ◽  
Relative Concentration ◽  
Elongation Factor ◽  
Experimental System ◽  
Rice Stripe Virus ◽  
Strong Positive Correlation ◽  
Significant Difference ◽  
Grade Scale ◽  
New Formula

Rice stripe virus (RSV) is one of the most devastating pathogens of rice (Oryza sativa) in rice-growing regions of East Asia. We analyzed the increase in RSV accumulation in infected rice plants over time and evaluated the association between disease severity and RSV accumulation with the aim of establishing an experimental system for accurate and efficient evaluation of RSV resistance in rice. As an index of RSV accumulation in plants, relative concentration of RNA corresponding to the coat protein gene region was measured using reverse-transcription quantitative polymerase chain reaction. Actin and elongation factor 1a were used as the host reference genes. RSV concentrations tended to increase with time from 7 to 28 days after inoculation, and a strong positive correlation was observed between the log RSV concentrations in the midsections of the uppermost leaves and in the stems at the first leaf sheath position. We analyzed RSV concentrations at these two locations 21 days after inoculation with RSV and assessed severity of disease symptoms based on a commonly used scale (Washio’s six-grade scale) rated as A (most severe), B, Bt, C, Cr, or D (mild symptoms). RSV concentrations at both locations were high in plants graded A, B, or Bt, with no significant difference in concentration of RSV among the three grades, but concentrations were significantly higher in the three grades compared with that in the plants in grade D. RSV concentrations were highly variable among plants in grades C and Cr. On the basis of these data, we propose a new formula to estimate the range of disease severities with greater ease and practical value. The values calculated by the new formula corresponded well to those based on Washio’s six-grade scale.

Association of APC and MCC Polymorphisms with Increased Breast Cancer Risk in an Indian Population

2011 ◽  
Vol 26 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Nupur Mukherjee ◽  
Nilanjana Bhattacharya ◽  
Satyabrata Sinha ◽  
Neyaz Alam ◽  
Runu Chakravarti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Breast Cancer Patients ◽  
Increased Risk ◽  
Risk Of Cancer

The adenomatous polyposis coli (APC) and mutated in colorectal cancer (MCC) genes are key regulatory genes of the Wnt/β-catenin signaling pathway, which are independently involved in maintaining low levels of β-catenin in the cell. In addition to genetic and epigenetic alterations, some genetic polymorphisms in the genes associated with the Wnt signaling pathway have been reported to be associated with an increased risk of cancer, including breast cancer. In the present study we analyzed the association of genotype and haplotype status of two single nucleotide polymorphisms (SNPs), rs2229992 and rs11283943, in the APC and MCC genes, respectively, with an increased risk of breast carcinogenesis in a breast cancer and control population from eastern India. We observed a significant association of the rs11283943 SNP with increased breast cancer risk. Two specific haplotypes involving the minor allele of rs11283943 were found to be associated with an increased breast cancer risk. Kaplan-Meier curves showed a significant association of the 2–2 genotype (genotype homozygous for the rs11283943 minor allele) with decreased survival (p=0.045) of the breast cancer patients in our study, in particular patients with early-onset BC.

scholarly journals Double-Stranded-RNA-Activated Protein Kinase PKR Enhances Transcriptional Activation by Tumor Suppressor p53

1999 ◽  
Vol 19 (4) ◽  
pp. 2475-2484 ◽  
Author(s):  
Andrew R. Cuddihy ◽  
Suiyang Li ◽  
Nancy Wai Ning Tam ◽  
Andrew Hoi-Tao Wong ◽  
Yoichi Taya ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Transcriptional Activation ◽  
Kinase Inhibitor ◽  
Regulation Of Gene Expression ◽  
Temperature Sensitive ◽  
Tumor Suppressor P53 ◽  
Double Stranded Rna ◽  
Genes Encoding ◽  
Inducible Genes

ABSTRACT The tumor suppressor p53 plays a key role in inducing G1 arrest and apoptosis following DNA damage. The double-stranded-RNA-activated protein PKR is a serine/threonine interferon (IFN)-inducible kinase which plays an important role in regulation of gene expression at both transcriptional and translational levels. Since a cross talk between IFN-inducible proteins and p53 had already been established, we investigated whether and how p53 function was modulated by PKR. We analyzed p53 function in several cell lines derived from PKR+/+ and PKR−/− mouse embryonic fibroblasts (MEFs) after transfection with the temperature-sensitive (ts) mutant of mouse p53 [p53(Val135)]. Here we report that transactivation of transcription by p53 and G0/G1 arrest were impaired in PKR−/− cells upon conditions that ts p53 acquired a wild-type conformation. Phosphorylation of mouse p53 on Ser18 was defective in PKR−/− cells, consistent with an impaired transcriptional induction of the p53-inducible genes encoding p21WAF/Cip1 and Mdm2. In addition, Ser18 phosphorylation and transcriptional activation by mouse p53 were diminished in PKR−/− cells after DNA damage induced by the anticancer drug adriamycin or γ radiation but not by UV radiation. Furthermore, the specific phosphatidylinositol-3 (PI-3) kinase inhibitor LY294002 inhibited the induction of phosphorylation of Ser18 of p53 by adriamycin to a higher degree in PKR+/+ cells than in PKR−/− cells. These novel findings suggest that PKR enhances p53 transcriptional function and implicate PKR in cell signaling elicited by a specific type of DNA damage that leads to p53 phosphorylation, possibly through a PI-3 kinase pathway.

scholarly journals EGFR Polymorphism and Survival of NSCLC Patients Treated with TKIs: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Vladimir Jurisic ◽  
Vladimir Vukovic ◽  
Jasmina Obradovic ◽  
Lyudmila F. Gulyaeva ◽  
Nikolay E. Kushlinskii ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Association Studies ◽  
Meta Analysis ◽  
Growth Factor Receptor ◽  
Fixed Effect Model ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Ca Repeat ◽  
Meta Analyses ◽  
Nsclc Patients

Tyrosine kinase inhibitor- (TKI-) based therapy revolutionized the overall survival and the quality of life in non-small-cell lung cancer (NSCLC) patients that have epidermal growth factor receptor (EGFR) mutations. However, EGFR is a highly polymorphic and mutation-prone gene, with over 1200 single nucleotide polymorphisms (SNPs). Since the role of EFGR polymorphism on the treatment outcome is still a matter of debate, this research analyzed the available literature data, according to the PRISMA guidelines for meta-analyses. Research includes PubMed, Scopus, ISI Web of Science, and 14 of genome-wide association studies (GWAS) electronic databases in order to provide quantitative assessment of the association between ten investigated EGFR SNPs and the survival of NSCLC patients. The pooled HR and their 95% CI for OS and PFS for different EGFR polymorphisms using a random or fixed effect model based on the calculated heterogeneity between the studies was applied. The longest and the shortest median OSs were reported for the homozygous wild genotype and a variant allele carriers for rs712829 (-216G>T), respectively. Quantitative synthesis in our study shows that out of ten investigated EGFR SNPs (rs11543848, rs11568315, rs11977388, rs2075102, rs2227983, rs2293347, rs4947492, rs712829, rs712830, and rs7809028), only four, namely, rs712829 (-216G>T), rs11568315 (CA repeat), rs2293347 (D994D), and rs4947492, have been reported to affect the outcome of TKI-based NSCLC treatment. Of these, only -216G>T and variable CA repeat polymorphisms have been confirmed by meta-analysis of available data to significantly affect OS and PFS in gefitinib- or erlotinib-treated NSCLC patients.

scholarly journals A comprehensive model for the proliferation–quiescence decision in response to endogenous DNA damage in human cells

2018 ◽  
Vol 115 (10) ◽  
pp. 2532-2537 ◽  
Author(s):  
Frank S. Heldt ◽  
Alexis R. Barr ◽  
Sam Cooper ◽  
Chris Bakal ◽  
Béla Novák
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Kinase Inhibitor ◽  
Human Cells ◽  
Cyclin Dependent Kinase ◽  
Restriction Point ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Serum Stimulation ◽  
G1 Cells ◽  
External Stimuli

Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation–quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli.

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