Abstract
Topoisomerase I in eukaryotic cells is an important regulator of DNA topology. Its catalytic function is to remove positive or negative superhelical tension by binding to duplex DNA, creating a reversible single-strand break, and finally religating the broken strand. Proper maintenance of DNA topological homeostasis, in turn, is critically important in the regulation of replication, transcription, DNA repair, and other processes of DNA metabolism. One of the cellular processes regulated by the DNA topology and thus by Topoisomerase I is the formation of non-canonical DNA structures. Non-canonical or non-B DNA structures, including the four-stranded G-quadruplex or G4 DNA, are potentially pathological in that they interfere with replication or transcription, forming hotspots of genome instability. In this review, we first describe the role of Topoisomerase I in reducing the formation of non-canonical nucleic acid structures in the genome. We further discuss the interesting recent discovery that Top1 and Top1 mutants bind to G4 DNA structures in vivo and in vitro and speculate on the possible consequences of these interactions.
Highlights
Eukaryotic Topoisomerase I (Top1) is a type IB topoisomerase that binds to duplex DNAand cleaves a single strand initially forming a phospho-tyrosyl bond at the 30 end of the cleavedDNA
This study showed that the cleavage of duplex DNA by human Top1 is inhibited by the presence of intermolecular or intramolecular G4 structures, and that this inhibition is due to the binding of Top1 to G4 DNA
Given the significance of G4 DNA-forming sequences in the cancer-associated genome rearrangements, it is very important to study how the guanine-run containing sequences are converted into hotspots of genome instability
Summary
Eukaryotic Topoisomerase I (Top1) is a type IB topoisomerase that binds to duplex DNA (dsDNA). In absence of a functional RNase H2 complex, which initiates error-free ribonucleotide excision repair, Top1-mediated cleavage at single ribonucleotides embedded in a DNA strand leads to mutations and genome instability [5,6]. The role of Top as a component of the RNA polymerase complex and as a positive regulator of promoter escape and transcription elongation was described [9]. We review another seminal function of Top in reducing the formation of genotoxic DNA secondary structures. We discuss the recent findings indicating that Top is a high-affinity G4 DNA-binding protein and speculate on the functional outcome of such an interaction
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