Topoisomerase

Topoisomerases regulate DNA topology by resolving supercoils, knots, and catenanes generated during replication, transcription, chromatin remodeling, and other nucleic acid metabolic processes^[1]. Mechanistically, these enzymes cleave one DNA strand through TOP1/TOP3 enzymes or both strands through TOP2 enzymes, forming transient cleavage complexes that permit DNA relaxation, decatenation, or strand passage before religation^[1][2]. Human topoisomerases include TOP1, TOP1MT, TOP2A, TOP2B, TOP3A, and TOP3B, and these isoforms support genome stability, transcription, DNA replication, chromatin remodeling, and higher-order genome organization^[3]. Compared with type I enzymes that cleave one DNA strand, type II topoisomerases generate temporary double-strand breaks and therefore play central roles in chromosome segregation, replication stress resolution, and transcription-linked chromatin topology^[2][4]. Disease relevance arises when irreversible topoisomerase cleavage complexes become DNA-protein crosslinks coupled with DNA breaks, creating genomic damage associated with cancer and neurological disease^[3][5]. In cancer research, TOP2A is linked to proliferation and drug response, whereas TOP2B contributes to DNA rearrangements and double-strand break formation after TOP2 poison exposure^[6]. For experimental and therapeutic applications, topoisomerase inhibitors such as topotecan, irinotecan, etoposide, doxorubicin, and mitoxantrone stabilize cleavage complexes, induce DNA damage, and support studies of chemotherapy response, resistance, and genome repair pathways^[1][5][7].