Key Points
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Eukaryotic cells contain two distinct but interrelated pools of DNA precursors for the replication of nuclear and mitochondrial DNA. Deoxyribonucleoside triphosphate (dNTP) biosynthesis begins either with the reduction of ribonucleotides or with the salvage of preformed nucleosides or nucleobases.
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dNTP pool sizes are regulated mostly at the level of biosynthesis, particularly involving ribonucleotide reductase. However, controlled dNTP degradation brought about by the sterile α-motif and histidine-aspartate domain-containing protein (SAMHD1) protein has recently emerged as a major regulatory mechanism.
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An increase in the spontaneous mutation rate is almost certainly an essential feature of carcinogenesis. Abnormal regulation of dNTP pool sizes contributes to determination of the mutation rate.
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Several oncogenes and tumour suppressors control dNTP pool sizes and have as-yet-unexplained effects on oncogene-induced senescence.
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Much evidence indicates that 'sanitation', the enzymatic hydrolysis of abnormal or damaged nucleotides, is important to the maintenance of genomic stability. However, recent evidence indicates that one sanitizing enzyme, MTH1, is an important target for inhibition in cancer treatment.
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Many anticancer drugs achieve their effectiveness because they are analogues to DNA precursors. Effective use of these analogues requires a thorough understanding of nucleotide biosynthesis, transport processes, cell cycle regulation and interactions with target enzymes.
Abstract
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.
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Acknowledgements
The author thanks former students and colleagues who contributed to work cited from his laboratory, particularly L. Wheeler, K. Chimploy, I. Rajagopal, M. L. Tassotto and S. Martomo. He would also like to thank two anonymous referees for their help in improving this article. The author apologizes to those whose work he was unable to cite because of space limitations.
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Glossary
- Thymineless death
-
A loss of cell viability that occurs when an otherwise well-nourished cell is deprived of thymine nucleotides.
- Metastable
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Defining a state that does not represent thermodynamic equilibrium but that is nearly stable over the time frame of interest because progress towards equilibrium is slow.
- Mutator phenotype
-
A phenotype characterized by an abnormally high spontaneous mutation rate.
- Nucleobases
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A term used to define the purine and pyrimidine bases that are found in nucleic acids.
- Base excision repair
-
A DNA repair process that begins with cleavage of the glycosidic bond between a damaged base and the deoxyribose to which it is linked.
- Exergonic
-
Referring to a process or chemical reaction in a non-isolated system that proceeds with a net negative free energy change.
- Aicardi–Goutières syndrome
-
A rare inflammatory disorder, usually of early childhood onset, most typically affecting the brain and the skin; it arises as a result of mutations in one of at least seven human genes, including SAMHD1.
- Next-nucleotide effect
-
An increase in replication errors brought about by correct pairing between a template DNA base and an incoming deoxyribonucleotide that occurs before an upstream insertion error has been corrected by 3′-exonucleolytic proofreading.
- Replication stress
-
DNA damage endogenously generated by errors during DNA replication.
- Checkpoint
-
A point during the cell cycle at which the cell monitors its readiness to proceed into the next phase.
- Sliding clamp
-
A protein associated with replicative DNA polymerases that physically surrounds a DNA strand that is being replicated and prevents the dissociation of the polymerase until replication of the template has been completed.
- Free radical scavenger
-
A compound that can donate one electron to a compound containing a free radical and thereby convert an unpaired electron to an electron pair; a one-electron reductant.
- Transversion mutagenesis
-
A substitution mutation resulting from the change of a purine–pyrimidine base pair to a pyrimidine–purine base pair (for example, AT → CG).
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Mathews, C. Deoxyribonucleotide metabolism, mutagenesis and cancer. Nat Rev Cancer 15, 528–539 (2015). https://doi.org/10.1038/nrc3981
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DOI: https://doi.org/10.1038/nrc3981
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