TOP3B (DNA topoisomerase III beta) is a Type IA topoisomerase that catalyzes the transient cleavage and rejoining of single-stranded DNA and RNA, dissipating DNA supercoiling and resolving catenanes and knots 1. Unlike other human topoisomerases, TOP3B uniquely possesses RNA topoisomerase activity and primarily localizes to the cytoplasm, functioning as a non-canonical RNA-binding protein 2. Mechanistically, TOP3B employs general acid-base catalysis with a catalytic tyrosine forming a covalent DNA-(5'-phosphotyrosyl)-enzyme intermediate, facilitated by divalent metal ions and regulated by its cofactor TDRD3 13. Top3B plays critical roles in R-loop metabolism at gene promoters, where the TDRD3/TOP3B complex collaborates with DHX9 helicase to resolve R-loops and facilitate gene expression 4. Additionally, TOP3B regulates mRNA translation through its RBP function 2. Loss of TOP3B function leads to R-loop accumulation, genome instability, and DNA damage 5. Clinically, TOP3B mutations are associated with schizophrenia, autism, cognitive disorders, and cancer predisposition 65. TOP3B cleavage complexes are repaired via tyrosyl-DNA phosphodiesterase 2 (TDP2) and the TRIM41-proteasomal pathway 7.