DNA topoisomerase 1 (TOP1) and DNA topoisomerase 1, mitochondrial (TOP1MT) (TOP1 / TOP1MT)

DNA topoisomerase 1 (TOP1) and its mitochondrial paralog (TOP1MT) are essential enzymes that regulate the topological state of DNA by inducing transient single-strand breaks. These enzymes relieve the torsional strain, or supercoiling, that accumulates during critical cellular processes such as DNA replication, transcription, and repair in both the nucleus and the mitochondria (UniProt: P11387, Q969X2). In the nucleus, TOP1 is vital for genomic stability and is frequently overexpressed in various malignancies, making it a cornerstone target for cancer chemotherapy (PubMed: 11566134). The mitochondrial isoform, TOP1MT, is uniquely responsible for maintaining mitochondrial DNA (mtDNA) integrity and supporting mitochondrial protein synthesis, which is increasingly recognized as a factor in tumor growth and metabolic adaptation (PubMed: 22566610). Therapeutic agents, most notably the camptothecin derivatives irinotecan and topotecan, act as interfacial inhibitors by trapping the enzyme in a covalent complex with DNA (PubMed: 12140554). This stabilization prevents the religation of the DNA strand, leading to the formation of lethal double-strand breaks when the complex is encountered by advancing replication forks, ultimately triggering apoptosis in rapidly proliferating cancer cells (PubMed: 30214135). Beyond oncology, TOP1MT has been implicated in protecting against drug-induced cardiotoxicity, highlighting its broader physiological importance (PubMed: 25193121).

Other names

DNA topoisomerase 1DNA topoisomerase ITOP1TOP1MTMitochondrial DNA topoisomerase 1Topo IType IB topoisomerase

The primary mechanism of action for drugs targeting DNA topoisomerase 1 is the stabilization of the covalent topoisomerase I-DNA cleavage complex (TOP1cc). These drugs, known as topoisomerase I poisons, act as interfacial inhibitors by binding at the site of the DNA nick, preventing the religation of the DNA strand. When these stabilized complexes encounter advancing replication forks or transcription machinery, they are converted into permanent double-strand breaks, which trigger DNA damage response pathways and lead to programmed cell death (apoptosis) (PubMed: 22101209, PubMed: 30214135).