| Topoisomerase II alpha and beta, known as TOP2A and TOP2B, are type IIA topoisomerases that manage DNA topology by introducing transient double-strand breaks, passing another segment of DNA through the break, and then resealing it to resolve supercoiling and catenanes during processes like replication, transcription, and chromosome segregation. TOP2A is predominant in proliferating cells, especially during G2/M phase, and concentrates on mitotic chromatin to ensure proper chromosome condensation, chromatid cohesion, and anaphase decatenation, preventing chromosome bridges and segregation errors. It also partners with replication machinery such as MCM2-7 and the origin recognition complex at replication forks. TOP2B is expressed more broadly, peaks in late mitosis, and is important for differentiation, especially in neural cells. It relieves transcription-induced torsional stress, interacts with RNA polymerase II, and regulates developmental gene expression. Both enzymes have an N-terminal ATPase domain with Walker A and B motifs, a winged-helix DNA-binding domain, a TOPRIM core for DNA cleavage and religation with a key active site tyrosine, and isoform-specific C-terminal regions. ATP binding triggers N-gate closure and coordinates the DNA-gate for strand passage. Both enzymes are essential for maintaining genomic stability; overexpression of TOP2A is associated with various cancers, such as prostate and breast cancer, and is a target of chemotherapeutic agents like etoposide, while dysregulation of TOP2B is linked to neurodevelopmental disorders. |
