DNA topoisomerase II and DNA-dependent protein kinase (Top2 (for DNA topoisomerase II); DNA-PK (for DNA-dependent protein kinase))

DNA topoisomerase II is a ubiquitous, essential enzyme that modulates DNA topology by introducing transient double-stranded breaks to manage DNA tangles and supercoils during critical cellular processes like replication, transcription, and chromosome segregation. It acts as a homodimer, using ATP and magnesium as cofactors, and is composed of alpha (TOP2A) and beta (TOP2B) isoforms. Topoisomerase II is a validated target for a variety of widely used anticancer drugs: these drugs either trap the cleavage complex (topoisomerase II poisons) or inhibit the enzyme's catalysis, leading to DNA breakage and cell death in rapidly dividing cells. DNA-dependent protein kinase (DNA-PK) is a serine/threonine kinase and central enzyme in the non-homologous end joining pathway, mediating repair of DNA double-strand breaks. Inhibiting DNA-PK impairs DNA repair and sensitizes cells to DNA-damaging agents, expanding the effectiveness of topoisomerase II poisons to non-dividing, transcriptionally active cells, but can also increase normal tissue toxicity. Both enzymes are fundamental to genomic maintenance and cell survival, making them high-value targets in anticancer drug discovery and combination therapy. Combining their inhibition is promising but associated with increased on-target adverse effects.

Other names

Top2Topo IIDNA topoisomerase II alpha (TOP2A)DNA topoisomerase II beta (TOP2B)DNA-dependent protein kinasePRKDC (protein kinase, DNA-activated, catalytic polypeptide)DNA-PKcs (catalytic subunit)DNA-dependent protein kinase complex

Topoisomerase poisons stabilize the cleavable complex (DNA-enzyme complex with double-stranded break), leading to DNA breaks and cell death. Catalytic inhibitors block enzyme activity without stabilizing DNA breaks. Inhibitors of DNA-PK block repair of DNA double-strand breaks, increasing sensitivity to DNA-damaging agents such as Top2 poisons.