{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThymine DNA glycosylase (TDG) is a pivotal enzyme in maintaining genomic and epigenomic integrity. In its canonical role, TDG excises thymine from G·T mismatches that result from the deamination of 5‐methylcytosine and removes oxidized derivatives of 5‐methylcytosine—namely 5‐formylcytosine and 5‐carboxylcytosine—to initiate base excision repair (BER) and active DNA demethylation. These activities are essential not only for repairing mutagenic lesions but also for proper epigenetic reprogramming and embryonic development, with a pronounced preference for lesions in CpG dinucleotide contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDetailed biochemical, structural, and kinetic studies have unraveled the molecular mechanisms underlying TDG’s substrate recognition and catalytic proficiency. Investigations have revealed that specific active‐site residues and conformational changes—such as nucleotide flipping and water‐mediated coordination—facilitate efficient glycosidic bond cleavage while ensuring stringent specificity. In addition, the enzyme’s intrinsic tendency to remain bound to the abasic (AP) site is alleviated by auxiliary factors (for example, AP endonuclease 1) and post‐translational modifications like SUMO conjugation. High‐resolution crystallographic and molecular dynamics studies further illuminate how sequence context and substrate modifications influence TDG’s catalytic rate and product release."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its enzymatic functions, TDG serves as a hub for protein–protein interactions that integrate DNA repair with transcriptional regulation and chromatin remodeling. It interacts directly with components of the DNA damage checkpoint (such as the 9–1–1 complex), nuclear receptors including estrogen receptor α, and transcriptional coactivators like CBP/p300. These interactions are regulated by post‐translational modifications—SUMOylation, ubiquitination, and deacetylation by SIRT1—as well as by noncoding RNAs and auxiliary repair proteins (for example, NEIL1/2), which together modulate TDG’s stability, subcellular localization, and activity. Such multifaceted regulation underscores TDG’s role as a coordinator between base excision repair and epigenetic signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in TDG expression, genetic polymorphisms, or disruptions in its regulatory networks have been linked to carcinogenesis and therapeutic responses. For instance, aberrant TDG activity can lead to inefficient repair of mutagenic lesions or improper demethylation, thereby contributing to genomic instability observed in colorectal, breast, and melanoma cancers. 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