Nucleotide salvage, genome instability, and potential therapeutic applications.

Nucleotide salvage is crucial for maintaining DNA replication when de novo nucleotide synthesis is limited, but this metabolic flexibility poses potential threats to genome stability. Salvage kinases phosphorylate nucleosides broadly, allowing for oxidized and alkylated 2'-deoxynucleosides as well as posttranscriptionally modified ribonucleosides to enter the 2'-deoxynucleoside triphosphate (dNTP) pool. The ensuing contamination of the dNTP pool and the subsequent incorporation of modified nucleotides into genomic DNA promote mutagenesis, induce replication stress, elicit double-strand breaks, and disrupt epigenetic signaling. Although only a small subset of modified nucleosides have been assessed for salvage and genomic incorporation, the scope of salvageable substrates is probably much wider, with significant implications in mutational burden, chromatin instability, and epigenetic regulation. This overlooked aspect of genome instability is especially relevant in biological contexts of high salvage activity or elevated nucleoside damage, including chronic inflammation, cancer, aging, and dietary/microbiome exposures. Emerging evidence links salvage metabolism to tumor progression, where incorporation of salvage-derived nucleotides may contribute to unexplainable mutational signatures detected in cancers, such as gastrointestinal cancer. Recognizing salvage as a hidden source of mutagenesis reshapes our understanding of genome instability and provides potential opportunities for disease prevention, diagnosis, and therapeutic intervention.