DNA topoisomerase 1 (TOP1)

DNA topoisomerase 1 (TOP1) is an essential enzyme that manages the topological state of DNA by inducing transient single-strand breaks to relieve torsional strain during replication and transcription. It exists in two primary isoforms: the nuclear TOP1, which acts on the nuclear genome, and the mitochondrial TOP1MT, which is specifically required for mitochondrial DNA homeostasis (UniProt P11387, Q969P6). During its catalytic cycle, the enzyme forms a transient covalent intermediate known as the TOP1-DNA cleavage complex (TOP1cc). This complex is the specific target of camptothecin-derived chemotherapeutics, which trap the enzyme on the DNA, preventing the religation of the strand (Pommier, 2013, Nature Reviews Cancer). These trapped complexes act as bulky DNA lesions that collide with replication forks, resulting in lethal double-strand breaks and subsequent apoptosis in cancer cells. Consequently, TOP1 is a validated therapeutic target in various solid tumors, including colorectal, lung, and breast cancers.

Other names

Topoisomerase ITOP1MTDNA topoisomerase IMitochondrial DNA topoisomerase IScl-70 antigenDNA topoisomerase 1, nuclearDNA topoisomerase 1, mitochondrial

Inhibition of DNA religation by stabilizing the covalent DNA-topoisomerase I cleavage complex (TOP1cc), leading to lethal DNA double-strand breaks during replication fork collision.