DNA topoisomerase 1 - DNA cleavage complex (Top1cc)

DNA topoisomerase 1 (Top1) is an essential nuclear enzyme that regulates DNA topology by inducing transient single-strand breaks, allowing DNA to rotate and relieve torsional strain during replication and transcription (NIH, 2020). The Top1-DNA cleavage complex (Top1cc) is the catalytic intermediate where the enzyme is covalently attached to the 3-prime phosphate end of the DNA (MDPI, 2020). This complex is the primary molecular target for anticancer agents known as Top1 poisons, such as irinotecan and topotecan, which act as interfacial inhibitors by binding at the enzyme-DNA interface to stabilize the Top1cc (NIH, 1998; AACR, 2020). Stabilization prevents DNA religation, leading to lethal double-strand breaks when replication forks or transcription complexes collide with the trapped enzyme (Wikipedia, 2020). Beyond cancer, Top1 is a target of autoantibodies in systemic sclerosis, indicating its role in autoimmune pathology (NIH, 2020). Clinical response to Top1 inhibitors is often influenced by biomarkers like SLFN11 expression and the activity of repair enzymes such as TDP1 (AACR, 2020). However, these therapies are associated with significant safety concerns, including severe gastrointestinal toxicity and myelosuppression (NIH, 2020).

Other names

Topoisomerase ITOP1Top1-DNA covalent complexTop1 cleavage complexTop1-DNA CC

Interfacial inhibition; stabilization of the covalent Top1-DNA cleavage complex (Top1cc), preventing DNA religation and leading to replication-mediated double-strand breaks.