Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study

Siu, Fung‐Ming; Pommier, ﻿Yves

doi:10.1093/nar/gkt791

Cited by 11 publications

(10 citation statements)

References 75 publications

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“…CPT-induced DNA cleavage only occurred in the compacted DNA ( figure 3B ), reflecting that Top1 only acts on the compacted DNA and not on the relaxed DNA. In addition, we did not observe any specific sizes among the cleavage products of DNA other than the smear and the faint band on the gel ( figure 3B ), which is different from previous findings [21] . This result suggested no sequence preference for CPT to interact with Top1-DNAcc for the long length supercoil DNA.…”

Section: Discussioncontrasting

confidence: 99%

CFS-1686 Causes Cell Cycle Arrest at Intra-S Phase by Interference of Interaction of Topoisomerase 1 with DNA

Lin

Yang

et al. 2014

PLoS ONE

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CFS-1686 (chemical name (E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2-yl)vinyl)quinolin-4-ylamino)benzamide) inhibits cell proliferation and triggers late apoptosis in prostate cancer cell lines. Comparing the effect of CFS-1686 on cell cycle progression with the topoisomerase 1 inhibitor camptothecin revealed that CFS-1686 and camptothecin reduced DNA synthesis in S-phase, resulting in cell cycle arrest at the intra-S phase and G1-S boundary, respectively. The DNA damage in CFS-1686 and camptothecin treated cells was evaluated by the level of ATM phosphorylation, γH2AX, and γH2AX foci, showing that camptothecin was more effective than CFS-1686. However, despite its lower DNA damage capacity, CFS-1686 demonstrated 4-fold higher inhibition of topoisomerase 1 than camptothecin in a DNA relaxation assay. Unlike camptothecin, CFS-1686 demonstrated no activity on topoisomerase 1 in a DNA cleavage assay, but nevertheless it reduced the camptothecin-induced DNA cleavage of topoisomerase 1 in a dose-dependent manner. Our results indicate that CFS-1686 might bind to topoisomerase 1 to inhibit this enzyme from interacting with DNA relaxation activity, unlike campothecin's induction of a topoisomerase 1-DNA cleavage complex. Finally, we used a computer docking strategy to localize the potential binding site of CFS-1686 to topoisomerase 1, further indicating that CFS-1686 might inhibit the binding of Top1 to DNA.

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Section: Discussioncontrasting

confidence: 99%

CFS-1686 Causes Cell Cycle Arrest at Intra-S Phase by Interference of Interaction of Topoisomerase 1 with DNA

Lin

Yang

et al. 2014

PLoS ONE

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“…Secondly, the experiment with topoisomerase IIα (Topo IIα) was conducted and resulted in observation that PDZ-7 also inhibits Topo IIα in vitro , fully preventing kinetoplast DNA (kDNA) decatenation at concentrations of 5 μM or higher (Figure 2C ). However, PDZ-7 did not induce DNA cleavage as efficiently as etoposide (VP-16), a non-intercalative topoisomerase poison [ 25 ] (Figure 2D ). A faint band corresponding to linear pBR322 plasmid was observed only at 1 μM and not at higher or lower concentrations of PDZ-7 (Figure 2D ).…”

Section: Resultsmentioning

confidence: 99%

Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7

et al. 2017

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Anthrapyridazones, imino analogues of anthraquinone, constitute a family of compounds with remarkable anti-cancer activity. To date, over 20 derivatives were studied, of which most displayed nanomolar cytotoxicity towards broad spectrum of cancer cells, including breast, prostate and leukemic ones. BS-154, the most potent derivative, had IC50 values close to 1 nM, however, it was toxic in animal studies. Here, we characterize another anthrapyridazone, PDZ-7, which retains high cytotoxicity while being well tolerated in mice. PDZ-7 is also active in vivo against anthracycline-resistant tumor in a mouse xenograft model and induces DNA damage in proliferating cells, preferentially targeting cells in S and G2 phases of the cell cycle. Activation of Mre11-Rad50-Nbs1 (MRN) complex and phosphorylation of H2AX suggest double-stranded DNA breaks as a major consequence of PDZ-7 treatment. Consistent with this, PDZ-7 treatment blocked DNA synthesis and resulted in cell cycle arrest in late S and G2 phases. Analysis of topoisomerase IIα activity and isolation of the stabilized covalent topoisomerase IIα - DNA complex in the presence of PDZ-7 suggests that this compound is a topoisomerase IIα poison. Moreover, PDZ-7 interfered with actin polymerization, thereby implying its action as a dual inhibitor of processes critical for dividing cells. Using nuclear magnetic resonance (NMR) spectroscopy we show that PDZ-7 interacts with DNA double helix and quadruplex DNA structure. Taken together, our results suggest that PDZ-7 is a unique compound targeting actin cytoskeleton and DNA.

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“…However, a significant level of cleavage occurs when the −1 position is a C residue [18]. When the Top1 cleavage sites are analyzed by trapping the cleavage complex with the Top1 poison camptothecin (CPT), the sites of strong preference are clearly shifted from its preferential cleavage site in the absence of the intercalating drug [19]. CPT-intercalation into the DNA-Top1 complex requires T at the −1 position and prefers G at the +1 position.…”

Section: Top1 Binding Of Duplex Dnamentioning

confidence: 99%

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

Berroyer

Kim

2020

Genes

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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.

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Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study

Cited by 11 publications

References 75 publications

CFS-1686 Causes Cell Cycle Arrest at Intra-S Phase by Interference of Interaction of Topoisomerase 1 with DNA

CFS-1686 Causes Cell Cycle Arrest at Intra-S Phase by Interference of Interaction of Topoisomerase 1 with DNA

Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7

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

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