Pathways controlling dNTP pools to maintain genome stability.
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.
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.
Sean G
SG
Rudd
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Nicholas C K
NCK
Valerie
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Electronic address: thomas.helleday@scilifelab.se.
Thomas
T
Helleday
D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D009694:Nucleic Acid Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009711:Nucleotides / Q000096:biosynthesis* / Q000737:chemistry; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D000096964:Nudix Hydrolases
D004247:DNA; D045643:DNA Repair Enzymes; D009694:Nucleic Acid Precursors; D009711:Nucleotides; D010744:Phosphoric Monoester Hydrolases; D011755:Pyrophosphatases; D000096964:Nudix Hydrolases; C078207:8-oxodGTPase
DNA polymerase; DNA repair; Genome stability; MTH1; Oxidised nucleotides; dNTP pool sanitation