{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman topoisomerase I (TOP1) plays a pivotal role in maintaining genome integrity by relieving the torsional stress generated during DNA replication, transcription, and chromatin condensation. The enzyme acts by catalyzing a transient single‐strand break, which permits controlled rotation of the DNA and subsequent religation to restore continuity. High‐resolution structural studies have shown that anticancer drugs such as camptothecin and its derivatives intercalate at the TOP1–DNA cleavage site, stabilizing a covalent enzyme–substrate intermediate and thereby preventing religation—a mechanism that underpins their cytotoxicity. In addition, TOP1 activity is finely tuned during transcription; it becomes fully active only after RNA polymerase II is released from promoter‐proximal pausing, and kinetic analyses have revealed that subtle alterations in protein dynamics or mutations can markedly affect its religation step and thus drug sensitivity."}, {"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": "\nTOP1 function is intricately regulated by post‐translational modifications and the actions of dedicated repair pathways. Transient sumoylation—often involving the assembly of poly‐SUMO1 chains—modulates the enzyme’s subnuclear distribution and impacts its DNA binding, thereby precluding aberrant localization (for example, within nucleoli) under basal or DNA damage conditions. When TOP1–DNA cleavage complexes are stabilized by drugs or oxidative lesions, the ubiquitin–proteasome system is engaged to degrade the covalently bound enzyme, unveiling single‐strand breaks that can then be processed. Enzymes such as tyrosyl–DNA phosphodiesterase 1 (TDP1) and additional DNA damage response factors act in concert to resolve these toxic intermediates, with checkpoint kinases like ATR further influencing the cellular tolerance to TOP1‐mediated lesions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical catalytic role, TOP1 is involved in a variety of specialized cellular processes that bear significant clinical implications. Under conditions of oxidative stress, for example, reactive oxygen species can induce modifications that trap TOP1 on DNA, a phenomenon linked to cellular toxicity and even neurodegeneration. Moreover, the cellular response to TOP1 inhibitors is modulated by tumor suppressor status—with p53 disruption rendering cells markedly more sensitive to TOP1‐induced apoptosis—and by interactions with viral and host factors. TOP1 also participates in noncanonical functions: it associates with RNA‐binding proteins and long non‐coding RNAs (such as NORAD) to assemble ribonucleoprotein complexes that help maintain genomic stability; a specialized mitochondrial isoform regulates mitochondrial DNA replication; and TOP1 cleavage events have been implicated in generating mutation signatures that contribute to genome instability. Additional layers of regulation involve the modulation by PARP1 and chromatin remodelers, as well as crosstalk with transcriptional regulators (e.g. via hyperphosphorylation of RNA polymerase II components). These multifaceted roles are exploited therapeutically—not only by classic TOP1 poisons such as camptothecin and its derivatives (or by novel agents like betulinic acid and lamellarin D) but also through combination strategies aimed at enhancing anti‐tumor activity and even suppressing deleterious inflammatory responses observed in severe viral infections."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Diem-Thu Thieu Lesher, Yves Pommier, Lance Stewart, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-13-3369"}], "href": "https://doi.org/10.1158/0008-5472.CAN-13-3369"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25269479"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25269479"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Shar-Yin Naomi Huang, Sanchari Ghosh, Yves Pommier "}, {"type": "b", "children": [{"type": "t", "text": "Topoisomerase I alone is sufficient to produce short DNA deletions and can also reverse nicks at ribonucleotide sites."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.653345"}], "href": "https://doi.org/10.1074/jbc.M115.653345"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25887397"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25887397"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Subhendu K Das, Ishita Rehman, Arijit Ghosh, et al. 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