Folate and its derivatives are pivotal for cell cycle and proliferation. They facilitate the crosstalk between DNA synthesis and methylation crucial processes in cancer establishment . Dietary folate or supplements (e.g., folic acid) must be fully reduced by dihydrofolate reductase (DHFR) before entering cell metabolism . DHFR is responsible for dihydrofolate (DHF) to tetrahydrofolate (THF) conversion, as well as for assisting the generation of additional partially reduced folates (i.e., methylene-THF and formyl-THF), which are then transformed into the fully active folate (i.e., methyl-THF) with the help of methylenetetrahydrofolate reductase (MTHFR). As the main folate isoforms involved in DNA synthesis and methylation are handled by these two key enzymes, alterations in DHFR and/or in MTHFR functions may have detrimental effects on DNA stability and cancer susceptibility [2-5].
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