| Topic | Key findings | Primary citation IDs |
|---|---|---|
| Identity | • UniProt P11388 corresponds to **human TOP2A / DNA topoisomerase IIα**, a type IIA topoisomerase.
• Homodimeric, ATP-dependent nuclear enzyme with N-terminal ATPase, central catalytic core, and C-terminal regulatory/chromatin-tethering region. | (pqac-00000003, pqac-00000006) |
| Catalytic reaction / mechanism | • Catalyzes **ATP-dependent double-strand passage**: binds a gate (G) DNA segment, cleaves both strands, passes a transported (T) duplex through, then religates DNA.
• Uses an active-site **tyrosine** to form a covalent **5′-phosphotyrosyl TOP2A-DNA intermediate** during transient DSB formation.
• Mg2+ and ATP hydrolysis drive conformational changes and completion of the catalytic cycle. | (pqac-00000003, pqac-00000006, pqac-00000011) |
| Substrates / specificity | • Primary DNA-topology functions are **decatenation of intertwined sister DNAs** and **relaxation of positive/negative supercoils**.
• Supports chromosome structural integrity and resolution of DNA entanglements generated during replication/mitosis rather than sequence-specific DNA recognition. | (pqac-00000001, pqac-00000006, pqac-00000007) |
| Localization / cell-cycle role | • Predominantly **nuclear**; enriched on mitotic chromosome axes/scaffold and required for chromosome condensation, individualization, and segregation.
• Expression is **cell-cycle regulated**, peaking in **G2/M**, and TOP2A remains chromosome-associated during mitosis.
• No evidence supports TOP2A as a mitochondrial topoisomerase in human cells. | (pqac-00000001, pqac-00000006, pqac-00000007) |
| Regulation / PTMs | • The **C-terminal domain (CTD)** contains nuclear localization information and a chromatin-tethering region important for mitotic chromosome binding.
• CTD undergoes diverse **post-translational modifications** that modulate catalytic activity and protein interactions.
• Function is linked to the **decatenation checkpoint** and influenced by **p53** status. | (pqac-00000003, pqac-00000002) |
| Drug targeting / poisons vs catalytic inhibitors | • **TOP2 poisons** (e.g., **etoposide, doxorubicin/adriamycin, amsacrine**) stabilize the cleavage complex after DNA breakage, increasing persistent DNA damage.
• **Catalytic inhibitors** (e.g., **ICRF-193**, merbarone, ATPase-directed agents) inhibit cycle progression without necessarily stabilizing covalent TOP2A-DNA complexes.
• Drug mechanism differences are central to efficacy, toxicity, and checkpoint responses. | (pqac-00000001, pqac-00000004, pqac-00000011) |
| Recent cancer genomics / prognostic statistics | • Review data across ~**24,000** solid tumors found **~4% TOP2A amplification**; among **4,903** tumors, **129 (2.6%)** showed **TOP2A-HER2 co-amplification**; >40% co-amplification reported in some breast/ovarian/gastroesophageal/pancreatic subsets.
• In **182 iCCA** patients, high TOP2A expression associated with worse OS/DSS/MFS (**all p < 0.0001**).
• Recurrent somatic variants such as **p.K743N** are linked to characteristic mutational signatures/genome instability. | (pqac-00000000, pqac-00000009, pqac-00000010) |
| Recent mechanistic cancer findings | • In **NSCLC**, TOP2A upregulation promoted migration, invasion, EMT, and survival; knockdown reduced these phenotypes, with effects tied to **Wnt/β-catenin/Wnt3a** signaling.
• In ovarian cancer, TOP2A knockdown caused **G1 arrest**, apoptosis, and reduced proliferation, with rescue implicating **AKT/mTOR** signaling.
• In endocrine-therapy-resistant ER+ breast cancer, **TOP2A** was upregulated (**log2FC 0.79, p = 0.0381**) and correlated with proliferation-associated recurrence risk. | (pqac-00000008, pqac-00000010) |
*Table: This table condenses the key functional annotation points for human TOP2A, covering its verified identity, enzymatic mechanism, localization, regulation, drug interactions, and recent cancer-related findings. It is useful as a compact evidence map linking core biology to clinically relevant research.*