Mechanisms of genotoxicity and impact on genome arising from folate depletion. The disruption in the folate one-carbon cycle alters the abundance of nucleotides (purines, dTMP, and dUMP) and metabolites necessary to catalyze methylation reactions (SAM, homocysteine). This triggers different mechanisms of DNA damage that impact both nuclear and mitochondrial genome biology to induce genomic instability. The link between folate depletion and formaldehyde biology remains speculative in mammalian cells, so it is not highlighted as a genotoxic mechanism. dUMP, deoxyuridine monophosphate.