DNA precursor metabolism and genomic stability

Intracellular concentrations of the four deoxyribonucleoside triphosphates (dNTPs) are closely regulated, and imbalances in the four dNTP pools have genotoxic consequences. Replication errors leading to mutations can occur, for example, if one dNTP in excess drives formation of a non-Watson-Crick base pair or if it forces replicative DNA chain elongation past a mismatch before DNA polymerase can correct the error by 3' exonuclease proofreading. This review focuses on developments since 1994, when the field was last reviewed comprehensively. Emphasis is placed on the following topics: 1) novel aspects of dNTP pool regulation, 2) dNTP pool asymmetries as mutagenic determinants, 3) dNTP metabolism and hypermutagenesis of retroviral genomes, 4) dNTP metabolism and mutagenesis in the mitochondrial genome, 5) chemical modification of nucleotides as a premutagenic event, 6) relationships between dNTP metabolism, genome stability, aging, and cancer.