TOP1 (DNA topoisomerase I) is an essential enzyme that manages DNA topology by transiently cleaving and rejoining single DNA strands, thereby releasing supercoiling and torsional tension introduced during replication and transcription 1. The enzyme forms a covalent DNA-(3'-phosphotyrosyl)-enzyme intermediate through its catalytic tyrosine, allowing controlled strand rotation around the intact phosphodiester bond to remove supercoils before religation restores the DNA backbone. Beyond canonical topoisomerase activity, TOP1 regulates circadian transcription of BMAL1 by modifying chr20 structure and functions as an RNA-binding protein that directly binds mRNAs, with RNA inhibiting TOP1 activity during RNAPII-dependent transcription 2. Clinically, TOP1 is the primary target of camptothecin-derived anticancer agents including irinotecan and topotecan 1. Newer derivatives like exatecan show enhanced TOP1 trapping and DNA damage compared to classical inhibitors 3. TOP1 inhibitor-containing antibody-drug conjugates (ADCs) have improved survival in metastatic breast cancer, though resistance-associated TOP1 mutations (S57C, R364H, W401C, G359E) emerge in ~13% of ADC-treated patients, mediating cross-resistance between sequential ADCs 4. Sequential dosing of TOP1 inhibitor-ADCs with PARP inhibitors represents a viable therapeutic strategy 5. Additionally, TOP1 inhibition suppresses lethal SARS-CoV-2-induced inflammation, suggesting repurposing potential 6. Genomic ribonucleotides cleaved by TOP1 generate PARP-trapping lesions relevant to PARP inhibitor sensitivity 7.