-
Annual Review of Biochemistry 1988
Review
Topics: Animals; DNA Replication; Deoxyribonucleotides
PubMed: 3052277
DOI: 10.1146/annurev.bi.57.070188.002025 -
Annual Review of Genetics 1991
Review
Topics: Animals; Deoxyribonucleotides; Mutagenesis
PubMed: 1812810
DOI: 10.1146/annurev.ge.25.120191.002011 -
Cell Cycle (Georgetown, Tex.) Nov 2019Deoxyribonucleotide metabolites (dNTPs) are the substrates for DNA synthesis. It has been proposed that their availability influences the progression of the cell cycle... (Review)
Review
Deoxyribonucleotide metabolites (dNTPs) are the substrates for DNA synthesis. It has been proposed that their availability influences the progression of the cell cycle during development and pathological situations such as tumor growth. The mechanism has remained unclear for the link between cell cycle and dNTP levels beyond their role as substrates. Here, we review recent studies concerned with the dynamics of dNTP levels in early embryos and the role of DNA replication checkpoint as a sensor of dNTP levels.
Topics: Animals; Cell Cycle; Cell Division; DNA Replication; Deoxyribonucleotides; Drosophila; Metabolic Networks and Pathways; Ovum
PubMed: 31544596
DOI: 10.1080/15384101.2019.1665948 -
Biochemistry Feb 2011To maintain genomic stability, ribonucleotide incorporation during DNA synthesis is controlled predominantly at the DNA polymerase level. A steric clash between the... (Review)
Review
To maintain genomic stability, ribonucleotide incorporation during DNA synthesis is controlled predominantly at the DNA polymerase level. A steric clash between the 2'-hydroxyl of an incoming ribonucleotide and a bulky active site residue, known as the "steric gate", establishes an effective mechanism for most DNA polymerases to selectively insert deoxyribonucleotides. Recent kinetic, structural, and in vivo studies have illuminated novel features about ribonucleotide exclusion and the mechanistic consequences of ribonucleotide misincorporation on downstream events, such as the bypass of a ribonucleotide in a DNA template and the subsequent extension of the DNA lesion bypass product. These important findings are summarized in this review.
Topics: Animals; Carbohydrate Metabolism; Catalytic Domain; DNA; DNA-Directed DNA Polymerase; Deoxyribonucleotides; Humans; Models, Molecular; Molecular Conformation; Substrate Specificity
PubMed: 21226515
DOI: 10.1021/bi101915z -
Mutation Research 1988Numerous studies have demonstrated that DNA-precursor pool imbalances are mutagenic and can modulate the lethality and mutagenicity of DNA-damaging agents. In addition,... (Review)
Review
Numerous studies have demonstrated that DNA-precursor pool imbalances are mutagenic and can modulate the lethality and mutagenicity of DNA-damaging agents. In addition, physical and chemical mutagens can induce alterations in DNA-precursor levels. Such findings suggest that regulation of intracellular concentrations of DNA precursors may be an important factor in environmental mutagenesis. In this article, results linking mutation and disturbances in DNA-precursor pools are reviewed.
Topics: Animals; Deoxyribonucleotides; Homeostasis; Humans; Mutagens; Mutation
PubMed: 3292903
DOI: 10.1016/0027-5107(88)90076-0 -
Environmental Mutagenesis 1982
Review
Topics: Animals; Bromodeoxyuridine; Cells, Cultured; Chromosome Aberrations; Cytosine Nucleotides; DNA Replication; Deoxyribonucleotides; Humans; Mutation; Purine Nucleotides; Thymine Nucleotides
PubMed: 6761109
DOI: 10.1002/em.2860040609 -
Biopolymers 1999Loss of a base in DNA, i.e., creation of an abasic site leaving a deoxyribose residue in the strand, is a frequent lesion that may occur spontaneously, or under the... (Review)
Review
Loss of a base in DNA, i.e., creation of an abasic site leaving a deoxyribose residue in the strand, is a frequent lesion that may occur spontaneously, or under the action of radiations and alkylating agents, or enzymatically as an intermediate in the repair of modified or abnormal bases. The abasic site lesion is mutagenic or lethal if not repaired. From a chemical point of view,the abasic site is an alkali-labile residue that leads to strand breakage through beta- and delta- elimination. Progress in the understanding of the chemistry and enzymology of abasic DNA largely relies upon the study of synthetic abasic duplexes. Several efficient synthetic methods have thus been developed to introduce the lesion (or a stable analogue) at defined position in the sequence. Physicochemical and spectroscopic examination of such duplexes, including calorimetry, melting temperature, high-field nmr and molecular modeling indicate that the lesion strongly destabilizes the duplex, although remaining in the canonical B-form with structural modifications strictly located at the site of the lesion. Probes have been developed to titrate the damage in DNA in vitro. Series of molecules have been devised to recognize specifically the abasic site, exhibiting a cleavage activity and mimicking the AP nucleases. Others have been prepared that bind strongly to the abasic site and show promise in potentiating the cytotoxic and antitumor activity of the clinically used nitrosourea (bis-chloroethylnitrosurea).
Topics: Antineoplastic Agents; Base Pair Mismatch; DNA; DNA Adducts; DNA Ligases; Deoxyribonucleotides; Models, Molecular; Molecular Structure
PubMed: 10898853
DOI: 10.1002/1097-0282(1999)52:2<65::AID-BIP1>3.0.CO;2-U -
Scientific Reports Nov 2015Endogenous ribonucleotides and deoxyribonucleotides are essential metabolites that play important roles in a broad range of key cellular functions. Their intracellular...
Endogenous ribonucleotides and deoxyribonucleotides are essential metabolites that play important roles in a broad range of key cellular functions. Their intracellular levels could also reflect the action of nucleoside analogues. We investigated the effects of 5-fluorouracil (5-FU) on ribonucleotide and deoxyribonucleotide pool sizes in cells upon exposure to 5-FU for different durations. Unsupervised and supervised artificial neural networks were compared for comprehensive analysis of global responses to 5-FU. As expected, deoxyuridine monophosphate (dUMP) increased after 5-FU incubation due to the inhibition of thymine monophosphate (TMP) synthesis. Interestingly, the accumulation of dUMP could not lead to increased levels of deoxyuridine triphosphate (dUTP) and deoxyuridine diphosphate (dUDP). After the initial fall in intracellular deoxythymidine triphosphate (TTP) concentration, its level recovered and increased from 48 h exposure to 5-FU, although deoxythymidine diphosphate (TDP) and TMP continued to decrease compared with the control group. These findings suggest 5-FU treatment caused unexpected changes in intracellular purine polls, such as increases in deoxyadenosine triphosphate (dATP), adenosine-triphosphate (ATP), guanosine triphosphate (GTP) pools. Further elucidation of the mechanism of action of 5-FU in causing these changes should enhance development of strategies that will increase the anticancer activity of 5-FU while decreasing its resistance.
Topics: Adenine Nucleotides; Cell Survival; Chromatography, Liquid; Cytosine Nucleotides; Deoxyribonucleotides; Fluorouracil; Guanine Nucleotides; Hep G2 Cells; Humans; Inhibitory Concentration 50; Metabolic Networks and Pathways; Models, Biological; Neural Networks, Computer; Ribonucleotides; Tandem Mass Spectrometry; Thymine Nucleotides; Uracil Nucleotides
PubMed: 26578061
DOI: 10.1038/srep16861 -
Chemistry, An Asian Journal Oct 2010
Topics: Chromatography, High Pressure Liquid; Deoxyribonucleotides; Kinetics; Rotaxanes; Thermodynamics; alpha-Cyclodextrins
PubMed: 20715189
DOI: 10.1002/asia.201000289 -
Antiviral Research May 2003Nucleoside chain terminators represent one of the most promising classes of antiviral drug for DNA viruses and retroviral infection; however, they have not been fully...
Nucleoside chain terminators represent one of the most promising classes of antiviral drug for DNA viruses and retroviral infection; however, they have not been fully explored against RNA viral polymerases. In this report, we investigate the notion of employing canonical 3'-deoxyribonucleoside triphosphates (3'-dNTPs) as a chain terminator for hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp). Using a HCV RNA transcript-dependent RNA elongating assay, we found that they inhibit NS5B RdRp with K(i) ranged from 0.7 to 23 microM. Additional structure-activity relationship studies showed that removal of 2'-hydroxyl group, elimination of ribose's 2',3'-carbon-carbon bond, or addition of 5-methyl group to a pyrimidine base is detrimental to 3'-dNTP's potency. Direct evidence was obtained that all four canonical 3'-dNTP are incorporated into elongating RNA chains and the incorporation terminates NS5B RdRp-catalyzed RNA synthesis. The K(i) values for each of 3'-dNTPs were determined in the single nucleotide incorporation experiments. The nucleoside form of 3'-dNTPs was further evaluated in a cell culture-based HCV subgenomic replicon assay. The discrepancy between the potent in vitro activity and the weak cellular activity of these chain terminators was discussed in the context of nucleoside metabolism. This proof of concept study demonstrates that canonical 3'-dNTPs can function as an effective chain terminator for HCV NS5B RdRp with cytidine as the preferred nucleoside scaffold. Our results further sheds light on the potential hurdles that need to be overcome for successful development of active nucleoside chain terminators in vivo for a viral RNA polymerase, especially the HCV NS5B RdRp.
Topics: Cytidine; Deoxyribonucleotides; Hepacivirus; Humans; RNA, Viral; RNA-Dependent RNA Polymerase; Structure-Activity Relationship; Templates, Genetic; Tumor Cells, Cultured; Viral Nonstructural Proteins; Virus Replication
PubMed: 12767472
DOI: 10.1016/s0166-3542(03)00007-x