Pathways controlling dNTP pools to maintain genome stability. 2016

Sean G Rudd, and Nicholas C K Valerie, and Thomas Helleday
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Electronic address: sean.rudd@scilifelab.se.

Artificially modified nucleotides, in the form of nucleoside analogues, are widely used in the treatment of cancers and various other diseases, and have become important tools in the laboratory to characterise DNA repair pathways. In contrast, the role of endogenously occurring nucleotide modifications in genome stability is little understood. This is despite the demonstration over three decades ago that the cellular DNA precursor pool is orders of magnitude more susceptible to modification than the DNA molecule itself. More recently, underscoring the importance of this topic, oxidation of the cellular nucleotide pool achieved through targeting the sanitation enzyme MTH1, appears to be a promising anti-cancer strategy. This article reviews our current understanding of modified DNA precursors in genome stability, with a particular focus upon oxidised nucleotides, and outlines some important outstanding questions.

UI MeSH Term Description Entries
D009694 Nucleic Acid Precursors Use for nucleic acid precursors in general or for which there is no specific heading. Acid Precursors, Nucleic,Precursors, Nucleic Acid
D009711 Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. (From King & Stansfield, A Dictionary of Genetics, 4th ed) Nucleotide
D010084 Oxidation-Reduction A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). Redox,Oxidation Reduction
D010744 Phosphoric Monoester Hydrolases A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. Phosphatase,Phosphatases,Phosphohydrolase,Phosphohydrolases,Phosphomonoesterase,Phosphomonoesterases,Phosphoric Monoester Hydrolase,Hydrolase, Phosphoric Monoester,Hydrolases, Phosphoric Monoester,Monoester Hydrolase, Phosphoric
D011755 Pyrophosphatases A group of enzymes within the class EC 3.6.1.- that catalyze the hydrolysis of diphosphate bonds, chiefly in nucleoside di- and triphosphates. They may liberate either a mono- or diphosphate. EC 3.6.1.-. Pyrophosphatase
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004260 DNA Repair The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones. DNA Damage Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000096964 Nudix Hydrolases A group of Mg2+/Mn2+-dependent mainly pyrophosphohydrolases that hydrolyzes structures of NUcleoside DIphosphate linked to another moiety X to nucleoside monophosphate and X-Phosphate. Nudix hydrolases share conserved Nudix box (GX5EX7REUXEEXGU) and degrade variety of substrates including oxidized nucleotides (e.g., MutT) and metabolic intermediates (e.g., THIAMINE PYROPHOSPHATASE). In humans, Nudix superfamily proteins such as MutT proteins participate in DNA damage repairs. Mutations on a nudix hydrolase (NUDT15) are associated with a PURINE-PYRIMIDINE METABOLISM, INBORN ERRORS disorder called THPM2, and mutations in nudix hydrolase (NUDT2) are associated with IDDPN, a developmental intellectual disorder. Nucleoside Diphosphates-Linked to Moiety-X Hydrolases,Nudix Hydrolase,Nudix Proteins,Hydrolase, Nudix,Nucleoside Diphosphates Linked to Moiety X Hydrolases

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