{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman thymidine kinase 1 (TK1) is a pivotal enzyme in the thymidine salvage pathway that provides deoxythymidine triphosphate (dTTP) necessary for DNA synthesis. Its cellular levels are tightly regulated in a cell cycle–dependent manner—with markedly increased expression during the S and M phases and rapid proteolytic degradation during mitotic exit via the APC/C–Cdh1 pathway—thereby ensuring timely dTTP availability and preventing excess nucleotide formation in early G₁. TK1 activity is further fine‐tuned by post‐translational modifications, such as phosphorylation (e.g. at serine‑13), and by promoter elements including G-quadruplex motifs that modulate its transcription. In addition, responses to genotoxic stress (with differential effects in p53‑proficient versus p53‑deficient cells) can alter TK1’s subcellular localization and accumulation, supporting enhanced DNA repair during G₂ arrest."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and biochemical studies reveal that TK1 predominantly exists as a tetramer whose subunits comprise an α/β domain similar to ATPase folds. Crystallographic analyses have demonstrated that binding of dTTP exerts feedback inhibition through interactions involving main‐chain atoms, while ATP binding promotes tetramerization and thereby modulates its catalytic efficiency. Notably, structural comparisons indicate that type II TK1 differs fundamentally from other deoxyribonucleoside kinases, underscoring a unique evolutionary origin and substrate recognition mechanism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, aberrant TK1 expression—whether measured as mRNA, protein level, or enzyme activity—has been associated with increased cellular proliferation and is observed in a wide spectrum of malignancies including lung, breast, prostate, ovarian, cervical, melanoma, and soft tissue tumors. Numerous studies have demonstrated that both serum and tissue TK1 serve as robust diagnostic and prognostic biomarkers, correlating with tumor grade, stage, and response to various therapeutic modalities (such as CDK4/6 inhibitors and gene therapy approaches employing viral TK). In addition, TK1-based assays and imaging correlations (for example, with ³⁸F-FLT PET) have provided valuable information for cancer risk assessment, patient stratification and treatment monitoring, thereby highlighting the enzyme’s potential in routine cancer screening and personalized medicine."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chia-Lung Li, Ching-Yi Lu, Po-Yuan Ke, et al. 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