The Experts below are selected from a list of 177 Experts worldwide ranked by ideXlab platform
Paul W. Doetsch - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional mutagenesis and its potential roles in the etiology of cancer and bacterial antibiotic resistance
Journal of cellular physiology, 2013Co-Authors: Jordan Morreall, Lucy Petrova, Paul W. DoetschAbstract:Most cells do not undergo continuous cell division and DNA replication, yet they can still acquire novel RNA mutations that can result in the production of mutant proteins and induce a phenotypic change. All cells are frequently subjected to genotoxic insults that give rise to damaged nucleotides which, similarly to DNA replication, can undergo Base Mispairing during transcription. This mutagenic lesion bypass by RNA polymerase, transcriptional mutagenesis (TM), has been studied in a variety of systems and organisms, and may be involved in diverse pathogenic processes, such as tumorigenesis and the acquisition of bacterial antibiotic resistance. Tumor cells and bacteria within the human body are subject to especially high levels of oxidative stress, which can damage DNA and consequently drive TM. Mutagenesis at the level of transcription may allow cells to escape growth arrest and undergo replication that could permanently establish mutations in DNA in a process called retromutagenesis (RM). Here, we review the broad range of DNA damages which may result in TM including a variety of non-bulky lesions and some bulky lesions, which recent studies indicate may not completely block transcription, and emerging evidence supporting the RM concept in the context of tumorigenesis and antibiotic resistance. J. Cell. Physiol. 228: 2257–2261, 2013. © 2013 Wiley Periodicals, Inc.
Simon Wainhobson - One of the best experts on this subject based on the ideXlab platform.
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g a hypermutation of the human immunodeficiency virus type 1 genome evidence for dctp pool imbalance during reverse transcription
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Jeanpierre Vartanian, Andreas Meyerhans, Monica Sala, Simon WainhobsonAbstract:Abstract The quasispecies model for RNA viruses predicts the existence of a replication error threshold beyond which there is a melting or total loss of sequence information. Retroviral G-->A hypermutation is probably an example. Here it is shown that G-->A transitions may occur in both GpG and GpA dinucleotide contexts. Transitions in GpG preferentially occur via Base Mispairing at the ends of runs of G residues, whereas G-->A transitions within GpA may result from temporary dislocation of the primer and template strands by a single Base. The two circumstances may be related by the local dCTP substrate concentration. An in vitro elongation assay shows that primer/template dislocation is more frequent for the human immunodeficiency virus type 1 reverse transcriptase than for murine or avian retroviral enzymes. Taken together these data suggest that G-->A hypermutation is an example of induced mutation whereby the viral reverse transcriptase is forced into making errors by imbalances in the intracellular dCTP concentration.
Mutsuo Sekiguchi - One of the best experts on this subject based on the ideXlab platform.
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Activation of AMP-activated protein kinase by MAPO1 and FLCN induces apoptosis triggered by alkylated Base mismatch in DNA.
DNA repair, 2011Co-Authors: Teik How Lim, Mutsuo Sekiguchi, Ryosuke Fujikane, Shiori Sano, Ryuji Sakagami, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Masumi HidakaAbstract:O₆-methylguanine produced in DNA by the action of simple alkylating agents, such as N-methyl-N-nitrosourea (MNU), causes Base-Mispairing during DNA replication, thus leading to mutations and cancer. To prevent such outcomes, the cells carrying O⁶-methylguanine undergo apoptosis in a mismatch repair protein-dependent manner. We previously identified MAPO1 as one of the components required for the induction of apoptosis triggered by O⁶-methylguanine. MAPO1, also known as FNIP2 and FNIPL, forms a complex with AMP-activated protein kinase (AMPK) and folliculin (FLCN), which is encoded by the BHD tumor suppressor gene. We describe here the involvement of the AMPK-MAPO1-FLCN complex in the signaling pathway of apoptosis induced by O⁶-methylguanine. By the introduction of siRNAs specific for these genes, the transition of cells to a population with sub-G₁ DNA content following MNU treatment was significantly suppressed. After MNU exposure, phosphorylation of AMPKα occurred in an MLH1-dependent manner, and this activation of AMPK was not observed in cells in which the expression of either the Mapo1 or the Flcn gene was downregulated. When cells were treated with AICA-ribose (AICAR), a specific activator of AMPK, activation of AMPK was also observed in a MAPO1- and FLCN-dependent manner, thus leading to cell death which was accompanied by the depolarization of the mitochondrial membrane, a hallmark of the apoptosis induction. It is therefore likely that MAPO1, in its association with FLCN, may regulate the activation of AMPK to control the induction of apoptosis triggered by O⁶-methylguanine.
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Human proteins that specifically bind to 8-oxoguanine-containing RNA and their responses to oxidative stress.
Biochemical and biophysical research communications, 2010Co-Authors: Hiroshi Hayakawa, Aya Fujikane, Riyoko Ito, Masaki Matsumoto, Keiichi I. Nakayama, Mutsuo SekiguchiAbstract:Exposure of cells to oxygen radicals damage various biologically important molecules. Among the oxidized Bases produced in nucleic acids, 8-oxo-7,8-dihydroguanine (8-oxoguanine) is particularly important since it causes Base Mispairing. To ensure accurate gene expression, organisms must have a mechanism to discriminate 8-oxoguanine-containing RNA from normal transcripts. We searched for proteins that specifically bind to 8-oxoguanine-containing RNA from human HeLa cell extracts, and the candidate proteins were identified using mass spectrometry. Among the identified candidates, splicing isoform 1 of heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) and splicing isoform C1 of heterogeneous nuclear ribonucleoprotein C1/C2 (HNRNPC) exhibited strong abilities to bind to oxidized RNA. The amount of HNRNPD protein rapidly decreased when cells were exposed to hydrogen peroxide, an agent that enhances oxidative stress. Moreover, the suppression of HNRNPD expression by siRNA caused cells to exhibit an increased sensitivity to hydrogen peroxide. The application of siRNA against HNRNPC also caused an increase in sensitivity to hydrogen peroxide. Since no additive effect was observed with a combined addition of siRNAs for HNRNPD and HNRNPC, we concluded that the two proteins may function in the same mechanism for the accurate gene expression.
David E. G. Shuker - One of the best experts on this subject based on the ideXlab platform.
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Potassium diazoacetate-induced p53 mutations in vitro in relation to formation of O6-carboxymethyl- and O6-methyl-2'-deoxyguanosine DNA adducts: relevance for gastrointestinal cancer.
Carcinogenesis, 2006Co-Authors: Elke Gottschalg, Gina B. Scott, Philip A. Burns, David E. G. ShukerAbstract:Nitrosated glycine derivatives react with DNA to form O6-carboxymethyl-2'-deoxyguanosine (O6-CMdG) and O6-methyl-2'-deoxyguanosine (O6-MedG) adducts concurrently. O6-CMdG is not repaired by O6-alkylguanine alkyltransferases and might be expected to lead to mutations via a similar mechanism to O6-MedG. Potassium diazoacetate (KDA) is a stable form of nitrosated glycine and its ability to induce mutations in the p53 gene in a functional yeast assay was studied. Treatment of a plasmid containing the human p53 cDNA sequence with KDA afforded readily detectable levels of O6-CMdG and O6-MedG. The treated plasmid was used to transform yeast cells and coloured colonies harbouring a p53 sequence with functional mutations were detected. Recovery of the mutated plasmids followed by DNA sequencing enabled the mutation spectrum of KDA to be characterised. The most common mutations induced by KDA were substitutions with >50% occurring at GC Base pairs. In contrast to the methylating agent methylnitrosourea which gives predominantly (>80%) GCAT transitions, KDA produced almost equal amounts of transitions (GCAT) and transversions (GCTA and ATTA). This difference is probably due to a different mode of Base Mispairing for O6-CMdG compared with O6-MedG. The pattern of mutations induced by KDA was very similar to the patterns observed in mutated p53 in human gastrointestinal tract tumours. These results are consistent with the hypothesis that nitrosation of glycine (or glycine derivatives) may contribute to characteristic human p53 mutation profiles. This conclusion is borne out by recent observations that O6-CMdG is present in human DNA both from blood and exfoliated colorectal cells and is consistent with recent epidemiological studies that have concluded that endogenous nitrosation arising from red meat consumption is related to an increased risk of colorectal cancer.
Hiroshi Hayakawa - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional mutagenesis mediated by 8-oxoG induces translational errors in mammalian cells.
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Da Peng Dai, Wei Gan, Hiroshi Hayakawa, Jia Lou Zhu, Xiuqing Zhang, Zhe Li Jiang, Li-qun ZhangAbstract:Reactive oxygen species formed within the mammalian cell can produce 8-oxo-7,8-dihydroguanine (8-oxoG) in mRNA, which can cause Base Mispairing during gene expression. Here we found that administration of 8-oxoGTP in MTH1-knockdown cells results in increased 8-oxoG content in mRNA. Under this condition, an amber mutation of the reporter luciferase is suppressed. Using second-generation sequencing techniques, we found that U-to-G changes at preassigned sites of the luciferase transcript increased when 8-oxoGTP was supplied. In addition, an increased level of 8-oxoG content in RNA induced the accumulation of aggregable amyloid β peptides in cells expressing amyloid precursor protein. Our findings indicate that 8-oxoG accumulation in mRNA can alter protein synthesis in mammalian cells. Further work is required to assess the significance of these findings under normal physiological conditions.
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Human proteins that specifically bind to 8-oxoguanine-containing RNA and their responses to oxidative stress.
Biochemical and biophysical research communications, 2010Co-Authors: Hiroshi Hayakawa, Aya Fujikane, Riyoko Ito, Masaki Matsumoto, Keiichi I. Nakayama, Mutsuo SekiguchiAbstract:Exposure of cells to oxygen radicals damage various biologically important molecules. Among the oxidized Bases produced in nucleic acids, 8-oxo-7,8-dihydroguanine (8-oxoguanine) is particularly important since it causes Base Mispairing. To ensure accurate gene expression, organisms must have a mechanism to discriminate 8-oxoguanine-containing RNA from normal transcripts. We searched for proteins that specifically bind to 8-oxoguanine-containing RNA from human HeLa cell extracts, and the candidate proteins were identified using mass spectrometry. Among the identified candidates, splicing isoform 1 of heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) and splicing isoform C1 of heterogeneous nuclear ribonucleoprotein C1/C2 (HNRNPC) exhibited strong abilities to bind to oxidized RNA. The amount of HNRNPD protein rapidly decreased when cells were exposed to hydrogen peroxide, an agent that enhances oxidative stress. Moreover, the suppression of HNRNPD expression by siRNA caused cells to exhibit an increased sensitivity to hydrogen peroxide. The application of siRNA against HNRNPC also caused an increase in sensitivity to hydrogen peroxide. Since no additive effect was observed with a combined addition of siRNAs for HNRNPD and HNRNPC, we concluded that the two proteins may function in the same mechanism for the accurate gene expression.