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FASEB Journal : Official Publication of... Sep 2014For >35 yr, we have known that the accuracy of DNA replication is controlled in large part by the relative concentrations of the 4 canonical deoxyribonucleoside... (Review)
Review
For >35 yr, we have known that the accuracy of DNA replication is controlled in large part by the relative concentrations of the 4 canonical deoxyribonucleoside 5'-triphosphates (dNTPs) at the replisome. Since this field was last reviewed, ∼8 yr ago, there has been increased understanding of the mutagenic pathways as they occur in living cells. At the same time, aspects of deoxyribonucleotide metabolism have been shown to be critically involved in processes as diverse as cell cycle control, protooncogene expression, cellular defense against HIV infection, replication rate control, telomere length control, and mitochondrial function. Evidence supports a relationship between dNTP pools and microsatellite repeat instability. Relationships between dNTP synthesis and breakdown in controlling steady-state pools have become better defined. In addition, new experimental approaches have allowed definitive analysis of mutational pathways induced by dNTP pool abnormalities, both in Escherichia coli and in yeast. Finally, ribonucleoside triphosphate (rNTP) pools have been shown to be critical determinants of DNA replication fidelity. These developments are discussed in this review article.
Topics: Animals; DNA Replication; Deoxyribonucleotides; Gene Expression Regulation; Humans; Metabolic Networks and Pathways; Mutagenesis
PubMed: 24928192
DOI: 10.1096/fj.14-251249 -
DNA and Cell Biology Dec 2004Mitochondrial DNA (mtDNA) depends on numerous nuclear encoded factors and a constant supply of deoxyribonucleoside triphosphates (dNTP), for its maintenance and... (Review)
Review
Mitochondrial DNA (mtDNA) depends on numerous nuclear encoded factors and a constant supply of deoxyribonucleoside triphosphates (dNTP), for its maintenance and replication. The function of proteins involved in nucleotide metabolism is perturbed in a heterogeneous group of disorders associated with depletion, multiple deletions, and mutations of the mitochondrial genome. Disturbed homeostasis of the mitochondrial dNTP pools are likely the underlying cause. Understanding of the biochemical and molecular basis of these disorders will promote the development of new therapeutic approaches. This article reviews the current knowledge of deoxyribonucleotide metabolism in relation to disorders affecting mtDNA integrity.
Topics: Animals; DNA, Mitochondrial; Deoxyribonucleotides; Humans
PubMed: 15684706
DOI: 10.1089/dna.2004.23.797 -
Chemical Society Reviews May 2004Deoxyribonucleotides, monomers of macromolecular DNA and the chemical matter of genes, have received surprisingly little attention among chemists and molecular... (Review)
Review
Deoxyribonucleotides, monomers of macromolecular DNA and the chemical matter of genes, have received surprisingly little attention among chemists and molecular biologists alike, although their origin, properties, and mechanism of enzyme-catalyzed formation bear unique chemical traits which are the basis of DNA replication. Apart from providing insights in bioorganic free radical chemistry, present interest in deoxyribonucleotides stems from the expected demand of hundreds of kilograms per year for DNA chips and antisense constructs used in gene therapy, difficult to produce by conventional methods. A novel approach towards deoxyribonucleotide, and hence DNA formation in a putative primordial 'RNA world' has also recently emerged.
Topics: Animals; Biomimetics; Catalysis; DNA; DNA Replication; DNA, Antisense; Deoxyribonucleotides; Deoxyribose; Evolution, Molecular; Genetic Therapy; Nucleic Acid Precursors; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Ribonucleotide Reductases
PubMed: 15103404
DOI: 10.1039/a907361b -
Cancer Letters Jan 2015Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs when an activated oncogene is expressed in a normal cell. OIS acts as a... (Review)
Review
Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs when an activated oncogene is expressed in a normal cell. OIS acts as a bona fide tumor suppressor mechanism by driving stable growth arrest of cancer progenitor cells harboring the initial oncogenic hit. OIS is often characterized by aberrant DNA replication and the associated DNA damage response. Nucleotides, in particular deoxyribonucleotide triphosphates (dNTPs), are necessary for both DNA replication and repair. Imbalanced dNTP pools play a role in a number of human diseases, including during the early stages of cancer development. This review will highlight what is currently known about the role of decreased nucleotide metabolism in OIS, how nucleotide metabolism leads to transformation and tumor progression, and how this pathway can be targeted as a cancer therapeutic by inducing senescence of cancer cells.
Topics: Biomarkers, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cellular Senescence; DNA Damage; DNA Repair; DNA Replication; Deoxyribonucleotides; Humans; Neoplasms; Neoplastic Stem Cells; Oncogenes; Signal Transduction
PubMed: 24486217
DOI: 10.1016/j.canlet.2014.01.017 -
Nature Reviews. Cancer Sep 2015Cancer was recognized as a genetic disease at least four decades ago, with the realization that the spontaneous mutation rate must increase early in tumorigenesis to... (Review)
Review
Cancer was recognized as a genetic disease at least four decades ago, with the realization that the spontaneous mutation rate must increase early in tumorigenesis to account for the many mutations in tumour cells compared with their progenitor pre-malignant cells. Abnormalities in the deoxyribonucleotide pool have long been recognized as determinants of DNA replication fidelity, and hence may contribute to mutagenic processes that are involved in carcinogenesis. In addition, many anticancer agents antagonize deoxyribonucleotide metabolism. Here, we consider the extent to which aspects of deoxyribonucleotide metabolism contribute to our understanding of both carcinogenesis and to the effective use of anticancer agents.
Topics: Cellular Senescence; Deoxyribonucleotides; Humans; Mutagenesis; Neoplasms; Oncogenes; Orphan Nuclear Receptors; Telomere
PubMed: 26299592
DOI: 10.1038/nrc3981 -
Seminars in Cell & Developmental Biology Jun 2014Synthesis of deoxynucleoside triphosphates (dNTPs) is essential for both DNA replication and repair and a key step in this process is catalyzed by ribonucleotide... (Review)
Review
Synthesis of deoxynucleoside triphosphates (dNTPs) is essential for both DNA replication and repair and a key step in this process is catalyzed by ribonucleotide reductases (RNRs), which reduce ribonucleotides (rNDPs) to their deoxy forms. Tight regulation of RNR is crucial for maintaining the correct levels of all four dNTPs, which is important for minimizing the mutation rate and avoiding genome instability. Although allosteric control of RNR was the first discovered mechanism involved in regulation of the enzyme, other controls have emerged in recent years. These include regulation of expression of RNR genes, proteolysis of RNR subunits, control of the cellular localization of the small RNR subunit, and regulation of RNR activity by small protein inhibitors. This review will focus on these additional mechanisms of control responsible for providing a balanced supply of dNTPs.
Topics: Active Transport, Cell Nucleus; Animals; Cell Cycle; DNA Repair; DNA Replication; Deoxyribonucleotides; Feedback, Physiological; Genomic Instability; Humans; Ribonucleotide Reductases
PubMed: 24704278
DOI: 10.1016/j.semcdb.2014.03.030 -
The Journal of Biological Chemistry Aug 2001Terminal deoxynucleotidyl transferase (TdT) catalyzes the condensation of deoxyribonucleotides on 3'-hydroxyl ends of DNA strands in a template-independent manner and...
Terminal deoxynucleotidyl transferase (TdT) catalyzes the condensation of deoxyribonucleotides on 3'-hydroxyl ends of DNA strands in a template-independent manner and adds N-regions to gene segment junctions during V(D)J recombination. Although TdT is able to incorporate a few ribonucleotides in vitro, TdT discrimination between ribo- and deoxyribonucleotides has never been studied. We found that TdT shows only a minor preference for incorporation of deoxyribonucleotides over ribonucleotides on DNA strands. However, incorporation of ribonucleotides alone or in the presence of deoxyribonucleotides generally leads to premature chain termination, reflecting an impeded accommodation of ribo- or mixed ribo/deoxyribonucleic acid substrates by TdT. An essential catalytic aspartate in TdT was identified, which is a first step toward understanding the apparent lack of sugar discrimination by TdT.
Topics: Catalysis; DNA Nucleotidylexotransferase; Deoxyribonucleotides; Recombination, Genetic; Ribonucleotides
PubMed: 11406636
DOI: 10.1074/jbc.M105272200 -
Analytical Biochemistry Mar 2019Quantification of cellular deoxyribonucleoside mono- (dNMP), di- (dNDP), triphosphates (dNTPs) and related nucleoside metabolites are difficult due to their...
Quantification of cellular deoxyribonucleoside mono- (dNMP), di- (dNDP), triphosphates (dNTPs) and related nucleoside metabolites are difficult due to their physiochemical properties and widely varying abundance. Involvement of dNTP metabolism in cellular processes including senescence and pathophysiological processes including cancer and viral infection make dNTP metabolism an important bioanalytical target. We modified a previously developed ion pairing reversed phase chromatography-mass spectrometry method for the simultaneous quantification and C isotope tracing of dNTP metabolites. dNMPs, dNDPs, and dNTPs were chromatographically resolved to avoid mis-annotation of in-source fragmentation. We used commercially available CN-stable isotope labeled analogs as internal standards and show that this isotope dilution approach improves analytical figures of merit. At sufficiently high mass resolution achievable on an Orbitrap mass analyzer, stable isotope resolved metabolomics allows simultaneous isotope dilution quantification and C isotope tracing from major substrates including C-glucose. As a proof of principle, we quantified dNMP, dNDP and dNTP pools from multiple cell lines. We also identified isotopologue enrichment from glucose corresponding to ribose from the pentose-phosphate pathway in dNTP metabolites.
Topics: Carbon Isotopes; Cells, Cultured; Chromatography, Liquid; Deoxyribonucleotides; Humans; Indicator Dilution Techniques; Isotope Labeling; Mass Spectrometry; Nitrogen Isotopes
PubMed: 30605633
DOI: 10.1016/j.ab.2018.12.023 -
Nature Genetics Apr 1996There are two biological properties of genomic methylation patterns that can be regarded as established. First, methylation of 5'-CpG-3' dinucleotides within promoters... (Review)
Review
There are two biological properties of genomic methylation patterns that can be regarded as established. First, methylation of 5'-CpG-3' dinucleotides within promoters represses transcription, often to undetectable levels. Second, in most cases methylation patterns are subject to clonal inheritance. These properties suit methylation patterns for a number of biological roles, although none of the current hypotheses can be regarded as proved or disproved. One hypothesis suggests that the activity of parasitic sequence elements is repressed by selective methylation. Features of invasive sequences that might allow their identification and inactivation are discussed in terms of the genome defense hypothesis. Identification of the cues that direct de novo methylation may reveal the biological role (or roles) of genomic methylation patterns.
Topics: Alleles; Animals; Base Composition; Cytosine; DNA; Deoxyribonucleotides; Female; Genome; Humans; Male; Meiosis; Methylation; Recombination, Genetic
PubMed: 8630488
DOI: 10.1038/ng0496-363 -
Annual Review of Genetics 1991
Review
Topics: Animals; Deoxyribonucleotides; Mutagenesis
PubMed: 1812810
DOI: 10.1146/annurev.ge.25.120191.002011