Topoisomerase IB: a relaxing enzyme for stressed DNA

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.

Keywords: Human DNA topoisomerase IB; drugs inhibition; mechanism of action.

Figure 1

Domain representation of hTopIB showing the catalytic pentad. HTopIB comprises an N-terminal domain (1-214; blue), a core domain (215-635; red), a linker domain (636-712; green), and a C-terminal domain (713-765; yellow). The black lines in the core and C-terminal domain highlight the residues that form the catalytic pentad^[17]

Figure 2

Schematic view of the 3D structure of the non-covalent hTopIB-DNA complex in two different orientations. A: Different domains and DNA forming the complex; B: core subdomains I and II forming the “Cap” region and the residues belonging to core subdomain III and the C-terminal domain forming the “Cat” region. At the top are two loops or lips and opposite to the lips are the chains of the “hinge” residues. This molecular picture was produced with UCSF Chimera program^[35]

Figure 3

The mechanism of action of hTopIB by controlled rotation. The figure shows the different steps of enzyme catalysis during DNA relaxation, starting from hTopIB binding to enzyme release. The magnification in the controlled rotation step represents the catalytic pentad. The enzyme core domain is in red, the linker is in green, the C-terminal domain is in yellow, and DNA is in blue. This molecular picture was produced with UCSF Chimera program^[35]

Figure 4

Schematic representation of the different steps of the hTopIB catalysis that can be affected by the inhibitor drugs: inhibition of binding (A); inhibition of cleavage (B); and inhibition of relegation (C). HTopIB is represented in green, while the drug is represented in red