Features of cancer cell metabolism linked to DNA repair mechanisms

Metabolic pathways in tumor cells can diverge significantly from the canonical pathways described for healthy tissues and cells. Although they involve the same proteins and substrate molecules, differences in metabolite concentrations, the skipping of only a few pathway participants, and alterations in downstream signaling processes and post-translational modifications of enzymes can lead to substantially altered cell morphology and function. In recent years, several novel and unexpected protein modifications caused by impaired tumor cell metabolism, as well as unusual roles of certain metabolic products, have been discovered. By integrating these new findings with current knowledge of DNA repair mechanisms, this review aims to discuss the latest discoveries regarding the peculiarities of tumor cell metabolism. This review examines the local supply of ATP, NAD⁺, acetyl-CoA and deoxyribonucleoside triphosphates at DNA damage sites. It also covers metabolite-driven modifications of repair proteins, with a focus on lysine lactylation. The discussion then shifts to the tumor microenvironment, where hypoxia, acidosis and nutrient limitation alter repair pathway choice. Finally, it considers the therapeutic window for targeting the metabolic enzymes involved. Such insights may prove valuable for future targeted drug development. We also argue that the subcellular compartmentalization and post-translational regulation described here limit how far metabolic inferences drawn from transcriptomes can be trusted. Metabolic pathways should therefore not be treated as distinct, static entities for analysis, since doing so may lead to missed opportunities to identify novel biomarkers or drug targets. The variability of metabolism in tumor cells is much greater than previously thought.