{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTOP2A (DNA topoisomerase IIα) is a critical enzyme that regulates DNA topology by catalyzing transient double‐stranded DNA breaks and re‐ligation to resolve supercoils and catenanes. Its dynamic activity is essential during DNA replication and mitosis, ensuring proper decatenation of newly replicated sister chromatids and accurate chromosome segregation. Structural and biochemical studies reveal that TOP2A markedly bends its DNA substrate and undergoes quantized conformational transitions—processes that depend on ATP hydrolysis—and that its association with centromeric and telomeric chromatin is modulated by chromatin‐remodeling factors and checkpoint effectors. Disruptions in TOP2A function can result in untimely anaphase bridges and cell cycle delays, ultimately compromising genomic integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant TOP2A expression and gene alterations are commonly observed in a wide spectrum of malignancies—including breast, hepatocellular, pancreatic, bladder, and adrenocortical cancers—and are frequently associated with aggressive tumor behavior and chemoresistance. Co‐amplification with oncogenes such as HER2, activation of pathways like β‐catenin signaling, and specific genomic gains contribute to its utility as a prognostic biomarker and predictor of treatment response, especially to anthracycline‐based therapies and other TOP2 inhibitors. Moreover, TOP2A dysregulation plays a role in leukemogenesis through its susceptibility to poisoning by metabolites such as 1,4‐benzoquinone, further emphasizing its relevance as a clinical target and as a key component in stratifying patients for individualized therapy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTherapeutic targeting of TOP2A has emerged as a promising strategy in cancer treatment. Novel small‐molecule inhibitors, including multitarget agents such as naphthalimides and nitidine chloride, have been developed to interfere with TOP2A’s catalytic cycle and promote the accumulation of lethal DNA lesions. In parallel, regulatory mechanisms—such as p21‐mediated transcriptional repression, isoform‐specific modifications, and modulation by RNA‐binding proteins—finely tune TOP2A expression and activity, thereby influencing drug sensitivity and apoptotic responses. Continued elucidation of TOP2A’s regulatory network and its interplay with DNA repair pathways is critical for optimizing chemotherapeutic regimens and overcoming treatment resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Morten O Christensen, Morten K Larsen, Hans Ullrich Barthelmes, et al. 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