Cloning and characterization of a mouse homologue (mnthl1) of Escherichia coli endonuclease III

Sarker, Altaf H.; Ikeda, Shogo; Nakano, Hironobu; Terato, Hiroaki; Ide, Hiroshi; Imai, Kotoe; Akiyama, Kosuke; Tsutsui, Ken; Zhang, Bo; Kubo, Kihei; Yamamoto, Kazuo; Yasui, Akira; Yoshida, Michihiro C.; Seki, Shuji

doi:10.1006/jmbi.1998.2042

Cited by 73 publications

(50 citation statements)

References 52 publications

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“…The sequence alignment of hNTH1 with NTHs from E. coli, archea and other lower organisms shows that the human (and other mammalian) NTH1 has an N-terminal tail, absent in E. coli and archea. This N-terminal tail (residues 1-95) contains putative nuclear and mitochondrial localization signals [170]. hNTH1 was found to have low activity compared to E. coli Nth [49,171].…”

Section: Unique Structural Features Of Mammalian Dna Glycosylasesmentioning

confidence: 99%

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

2008

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Base excision repair (BER) is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged (oxidized or alkylated) or inappropriate bases that are generated endogenously or induced by genotoxicants, predominantly, reactive oxygen species (ROS). BER involves 4-5 steps starting with base excision by a DNA glycosylase, followed by a common pathway usually involving an AP-endonuclease (APE) to generate 3′ OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and nick sealing by a DNA ligase. This pathway is also responsible for repairing DNA single-strand breaks with blocked termini directly generated by ROS. Nearly all glycosylases, far fewer than their substrate lesions particularly for oxidized bases, have broad and overlapping substrate range, and could serve as back-up enzymes in vivo. In contrast, mammalian cells encode only one APE, APE1, unlike two APEs in lower organisms. In spite of overall similarity, BER with distinct subpathways in the mammals is more complex than in E. coli. The glycosylases form complexes with downstream proteins to carry out efficient repair via distinct subpathways one of which, responsible for repair of strand breaks with 3′ phosphate termini generated by the NEIL family glycosylases or by ROS, requires the phosphatase activity of polynucleotide kinase instead of APE1. Different complexes may utilize distinct DNA polymerases and ligases. Mammalian glycosylases have nonconserved extensions at one of the termini, dispensable for enzymatic activity but needed for interaction with other BER and non-BER proteins for complex formation and organelle targeting. The mammalian enzymes are sometimes covalently modified which may affect activity and complex formation. The focus of this review is on the early steps in mammalian BER for oxidized damage.

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Section: Unique Structural Features Of Mammalian Dna Glycosylasesmentioning

confidence: 99%

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

2008

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“…Endonuclease III (EnIII ) can also cleave many pyrimidine derivatives, including thymine glycol, 5,6-dihydrothymine, 5-hydroxy dihydrothymine, 5-hydroxycytosine, 5-hydroxyuracil, and uracil glycol (12). These two enzymes revealed higher levels of DSB than did PK (13 …”

Section: Oxidative Dna Adducts Are Predominant and Prevalentmentioning

confidence: 99%

Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions induced by arsenite.

Bau

Wang

Chung

et al. 2002

Environ Health Perspect

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Arsenic is recognized to be a nonmutagenic carcinogen because it induces DNA damage only at very high concentrations. However, many more DNA strand breaks could be detected by digesting the DNA of arsenite-treated cells with endonuclease III, formamidopyrimidine-DNA glycosylase, and proteinase K. By doing so, arsenite could be shown to induce DNA damage in human cells within a pathologically meaningful concentration range. Oxidized guanine products were detected in all arsenite-treated human cells examined. DNA-protein cross-links were also detected in arsenite-treated NB4 and HL60 cells. In human umbilical vein endothelial cells, the induction of oxidized guanine products by arsenite was sensitive to inhibitors of nitric oxide (NO) synthase but not to oxidant modulators, whereas the opposite result was obtained in vascular smooth muscle cells. On the other hand, the arsenite-induced oxidized guanine products and DNA-protein cross-links in NB4 and HL60 cells were sensitive to modulators of calcium, NO synthase, oxidant, and myeloperoxidase. Therefore, although oxidized guanine products were detected in all the human cells treated with arsenite, the pathways could be different in different cell types. Because the sensitivity and the mechanism of arsenic intoxication are cell specific, it is important that target tissues and target cells are used for investigations. It is also important that pathologically or pharmacologically meaningful concentrations of arsenic are used. This is because in most cases we are dealing with the chronic effect rather than acute toxicity.

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“…An Nth orthlog has been cloned from Schizosaccharomyces pombe, Nth-Spo (10,11). The bovine, mouse, and human orthologs of EcoNth have also been cloned and the proteins characterized (12)(13)(14)(15)(16). Like EcoNth, hNTH1, bNth, and mNth1 possess DNAglycosylase/lyase activity on oxidized pyrimidines, formamidopyrimidines, and AP sites.…”

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confidence: 99%

Engineering Functional Changes in Escherichia coli Endonuclease III Based on Phylogenetic and Structural Analyses

Watanabe

Blaisdell

Wallace

et al. 2005

Journal of Biological Chemistry

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Escherichia coli endonuclease III (EcoNth) plays an important cellular role by removing premutagenic pyrimidine damages produced by reactive oxygen species. EcoNth is a bifunctional enzyme that has DNA glycosylase and apurinic/apyrimidinic lyase activities. Using a phylogeny of natural sequences, we selected to study EcoNth serine 39, aspartate 44, and arginine 184, which are presumed to be in the vicinity of the damaged base in the glycosylasesubstrate complex. These three amino acids are highly conserved among Nth orthologs, although not among homologous glycosylases, such as MutY, that have different base specificities and no lyase activity. To examine the role of these amino acids in catalysis, we constructed three mutants of EcoNth, in which Ser 39 was replaced with leucine (S39L), Asp 44 was replaced with valine (D44V), and Arg 184 was replaced with alanine (R184A), which are the corresponding residues in EcoMutY. We showed that EcoNth S39L does not have significant glycosylase activity for oxidized pyrimidines, although it maintained AP lyase activity. In contrast, EcoNth D44V retained glycosylase activity against oxidized pyrimidines, but the apparent rate constant for the lyase activity of EcoNth D44V was significantly lower than that of EcoNth, indicating that Asp 44 in EcoNth is required for ␤-elimination. Finally, EcoNth R184A maintained lyase activity but exhibited glycosylase specificity different from that of EcoNth. The functional consequences of each of these three substitutions can be rationalized in the context of high resolution protein structures. Thus phylogeny-based scanning mutagenesis has allowed us to identify novel roles for amino acids in the substrate binding pocket of EcoNth in base recognition and/or catalysis.Base excision repair evolved to protect cellular DNA against the deleterious effects of endogeneous metabolic processes and is highly conserved across species (for reviews, see Refs. 1-3). The initial step in the base excision repair pathway is the removal of a damaged pyrimidine or purine by cleavage of the N-glycosyl bond by a DNA glycosylase. The glycosylases that recognize oxidative damages also exhibit AP 2

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Cloning and characterization of a mouse homologue (mnthl1) of Escherichia coli endonuclease III

Cited by 73 publications

References 52 publications

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions induced by arsenite.

Engineering Functional Changes in Escherichia coli Endonuclease III Based on Phylogenetic and Structural Analyses

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