DNA Topoisomerase 1 (TOP1)

DNA Topoisomerase 1 (TOP1) is a critical nuclear enzyme responsible for maintaining DNA topology during essential cellular processes such as replication, transcription, and recombination [1]. It functions by inducing transient single-strand breaks in the DNA, allowing the strand to rotate and relieve torsional strain before the enzyme catalyzes religation [1, 2]. The specific site where the enzyme covalently binds to the DNA is known as the cleavage site, forming a transient TOP1-DNA covalent complex (TOP1cc) [2]. Therapeutic agents, most notably camptothecin derivatives like irinotecan and topotecan, target this complex by acting as interfacial inhibitors that bind at the DNA-enzyme interface [2, 3]. By stabilizing the TOP1cc, these drugs prevent the religation of the DNA strand, effectively trapping the enzyme on the DNA [2]. When advancing replication forks collide with these stabilized complexes, the single-strand breaks are converted into lethal double-strand breaks [2, 4]. This mechanism triggers DNA damage response pathways and ultimately leads to apoptosis, making TOP1 a cornerstone target in the treatment of various solid tumors, including colorectal and ovarian cancers [3, 5]. Resistance to these therapies is often linked to the expression of repair enzymes like Tyrosyl-DNA phosphodiesterase 1 (TDP1) or the loss of Schlafen 11 (SLFN11) [4, 6].

Other names

Topoisomerase ITOP1DNA topoisomerase 1DNA at topoisomerase I cleavage sitesTOP1-DNA covalent complexType IB topoisomerase

Interfacial inhibition of the DNA-Topoisomerase 1 covalent complex, which prevents DNA religation and leads to replication-mediated double-strand breaks [2, 3].