topoisomeraseI

Topoisomerase I (Top1) is an essential enzyme that modulates DNA topology by removing torsional stress generated during replication, transcription, and chromatin dynamics. By relieving negative supercoils ahead of transcription machinery, Top1 helps maintain genome integrity and proper gene expression.

Most metazoan and many viral Top1 enzymes are classified as DNA topoisomerase type IB. They act as monomers and catalyze a single-strand break in duplex DNA through a covalent 3'-phosphotyrosyl intermediate formed by a catalytic tyrosine. The free 5' end remains attached; the intact strand is allowed to rotate around the break (controlled rotation), relieving supercoils. The break is then religated, restoring the DNA backbone. The enzyme can relax both positive and negative supercoils, with efficiency influenced by torsional strain and sequence context. Bacterial Top1 enzymes, by contrast, are type IA and operate by a strand-passage mechanism using 5'-phosphotyrosyl intermediates.

Structural organization typically includes an N-terminal noncatalytic domain, a central core, a short flexible linker, and a C-terminal catalytic domain that contains the essential active site tyrosine. The domain arrangement supports DNA bending, strand cleavage, and religation required for catalytic turnover.

Top1 is a major target of anticancer drugs. Camptothecin and its derivatives (irinotecan, topotecan) stabilize the Top1–DNA cleavage complex, converting transient breaks into cytotoxic lesions. These inhibitors are used against several cancers; resistance can arise through changes in TOP1 expression, drug efflux, or DNA repair. In bacteria, Top1 homologs help balance negative supercoiling and can influence antibiotic sensitivity.