The Functional Consequences of Eukaryotic Topoisomerase 1 Interaction with G-Quadruplex DNA

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.

G-quadruplex–R-loop interactions and the mechanism of anticancer G-quadruplex binders

“…Interestingly, Topoisomerase I candirectly bind to G4 structures in vitro ( 125 , 126 ), localize to telomeres in yeast ( 127 ), cleave telomeric G-rich repeats ( 128 ). In addition, the enzyme activity is inhibited by G4 aptamers (reviewed in ( 129 )). Thus, the findings in yeast on the Sμ switch region may suggest a complex mechanism of G-loop regulation by topoisomerase I during transcription, which may involve the enzyme binding to G4 to recruit other factors, such as helicases, to resolve the structure and prevent gene rearrangements ( 124 ).…”

Topoisomerase I (TOP1) dynamics: conformational transition from open to closed states

“…The extreme thermostability of CsTOP1 is a unique property that can be exploited for further studies and more specifically for biophysical assays. In particular, CsTOP1 could be used further to solve other states of the enzyme during its topoisomerase reactions, or to solve the structure of CsTOP1 with particular substrates, such as G-quadruplexes 46 .…”

Low-frequency vibrational modes in G-quadruplexes reveal the mechanical properties of nucleic acids

“…that have shown to have more affinity for G4s than for double-helix conformations in experiments in vitro 8 and in vivo . 9 Particularly important amongst these proteins is the helicase protein encoded by the gene BLM, which is believed to undo G4s that are accidentally formed during recombination or replication. This gene is defective in Bloom's syndrome, a rare genetic disorder characterized by genomic instability and a very high incidence of cancer.…”