Mechanisms of genome instability from cellular folate stress

Folate is the key cofactor in one-carbon metabolism, a universal metabolic pathway crucial for supporting the biosynthesis of nucleotides, several amino acids, and key redox regulators. Mammals are unable to synthesize folate de novo, and folate deficiency can result from several causes, including restricted dietary intake, genetic defects in folate absorption and its metabolism, and exposure to antimetabolite drugs. The link between depletion of folates and genetic instability has long been the subject of research and is implicated in the pathogenesis of human diseases associated with folate deficiency. In this review, we will discuss the different genotoxic mechanisms arising from folate deficiency and the impact on genome stability. Increasing our understanding of this topic is crucial for interpreting possible links between genetic instability downstream of folate stress and the healthcare impact of folate deficiency.