{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThymidylate synthase (TYMS) is a pivotal enzyme in folate‐dependent de novo pyrimidine biosynthesis that catalyzes the conversion of deoxyuridine monophosphate (dUMP) into deoxy-thymidine monophosphate (dTMP) using 5,10-methylene-tetrahydrofolate as the methyl donor. This reaction is critical for DNA synthesis and repair, underpinning both cell proliferation and genome stability. In addition to its enzymatic role, TYMS exerts regulatory influence by binding its own mRNA and that of other key cell cycle regulators—such as p53 and members of the myc family—to modulate translation. These autoregulatory and feedback mechanisms contribute not only to the tight control of nucleotide pools but also, in certain contexts, to oncogenic transformation and apoptotic responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic variations in the TYMS gene—including differences in the promoter enhancer region (with variable numbers of 28‐bp tandem repeats and specific single nucleotide polymorphisms as well as 6‐bp deletions in the 3′‐untranslated region)—profoundly modulate its expression levels. Altered TYMS expression impacts the sensitivity to fluoropyrimidine agents (such as 5-fluorouracil and pemetrexed) and other antifolates (e.g. methotrexate), often correlating with clinical outcomes in diverse settings including colorectal, gastric, lung, and hematologic malignancies, as well as in inflammatory conditions like rheumatoid arthritis and psoriasis. Moreover, TYMS expression can be further influenced by gene amplification, as well as by post-transcriptional regulators such as microRNAs (for example, miR-192 and miR-215) and transcription factors like c-MYC and E2F. In addition, its interplay with folate metabolism is emerging as an important pharmacogenetic parameter to individualize treatment, since TYMS polymorphisms are associated with both drug resistance and toxicity. 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