Abstract
DNA topoisomerase I enzymes relieve the torsional strain in DNA; they are essential for fundamental molecular processes such as DNA replication, transcription, recombination, and chromosome condensation; and act by cleaving and then religating DNA strands. Over the past few decades, scientists have focused on the DNA topoisomerases biological functions and established a unique role of Type I DNA topoisomerases in regulating gene expression and DNA chromosome condensation. Moreover, the human enzyme is being investigated as a target for cancer chemotherapy. The active site tyrosine is responsible for initiating two transesterification reactions to cleave and then religate the DNA backbone, allowing the release of superhelical tension. The different steps of the catalytic mechanism are affected by various inhibitors; some of them prevent the interaction between the enzyme and the DNA while others act as poisons, leading to TopI-DNA lesions, breakage of DNA, and eventually cellular death. In this review, our goal is to provide an overview of mechanism of human topoisomerase IB action together with the different types of inhibitors and their effect on the enzyme functionality.
Highlights
Topoisomerase I (TopI) is a class of enzymes responsible for catalyzing the relaxation of supercoiled DNA during cell essential processes such as DNA replication, transcription, recombination, and chromosome condensation[1,2]
They are divided according to their structure and mechanism of action: Type IA includes bacterial and archaeal TopI[4], topoisomerase III[5], and reverse gyrase, whereas Type IB includes eukaryotic TopI and topoisomerase V[6]
This review focuses on human DNA topoisomerase IB and its mechanism of action
Summary
Topoisomerase I (TopI) is a class of enzymes responsible for catalyzing the relaxation of supercoiled DNA during cell essential processes such as DNA replication, transcription, recombination, and chromosome condensation[1,2]. The structure of the hTopIB (PDB ID 1A36) has been resolved based on different studies such as conservation of sequence, sensitivity to limited proteolysis, hydrodynamic properties, and fragment reconstitution experiments[16]. These studies indicate that the human enzyme is composed of 765 amino acid residues and subdivided into four distinct domains [Figure 1]: the N-terminal (1-214; represented in blue), the core (215-635; represented in red), the linker (636-712; represented in green), and the C-terminal domain (713-765; represented in yellow)[14,18]. The X-ray density was only interpretable beginning from residue 215; the entire N-terminal domain is still not crystallized
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