Deoxyribonucleotide pools and DNA integrity

Deoxyribonucleotide pools and DNA integrity refers to the homeostatic regulation of the four deoxyribonucleoside triphosphates (dNTPs) required for DNA synthesis and genome maintenance (Kohnken et al., 2015, PMID: 25913728). The precise balance of these pools is critical for the fidelity of DNA polymerases; imbalances or depletion can lead to increased mutagenesis, replication fork collapse, and double-strand breaks (Pai and Kearsey, 2017, PMID: 28257285). This biological process is a classic target in cancer therapy, where antimetabolites like 5-fluorouracil and hydroxyurea inhibit enzymes such as thymidylate synthase and ribonucleotide reductase to starve cells of DNA precursors (Mathews, 2015, PMID: 25417722). Furthermore, defects in dNTP pool regulation are implicated in mitochondrial DNA depletion syndromes and the aging process (Zhu et al., 2022, PMID: 35105635). Therapeutic strategies often exploit the 'thymineless death' phenomenon or replication stress to selectively eliminate rapidly dividing cells (Wilson et al., 2014, PMID: 24469071).

Other names

dNTP pool maintenanceDeoxyribonucleoside triphosphate metabolismDNA precursor regulationGenome integrity maintenance

Drugs targeting this process typically inhibit rate-limiting enzymes in dNTP biosynthesis (e.g., ribonucleotide reductase, thymidylate synthase), leading to dNTP pool depletion or imbalance, which induces replication stress, DNA damage, and apoptosis (Kohnken et al., 2015; Wilson et al., 2014).