The G-Quadruplex Ligand Telomestatin Impairs Binding of Topoisomerase IIIα to G-Quadruplex-Forming Oligonucleotides and Uncaps Telomeres in ALT Cells

Temime-Smaali, Nassima; Guittat, Lionel; Sidibe, Assitan; Shin‐ya, Kazuo; Trentesaux, Chantal; Riou, Jean‐François

doi:10.1371/journal.pone.0006919

Cited by 66 publications

(43 citation statements)

References 55 publications

(88 reference statements)

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“…Exposure of human cells to small molecules such as telomestatin (TMS) that specifically bind G4 structures in vitro induce the dissociation of shelterin proteins [e.g., protection of telomeres 1 (POT1) and TATA box binding protein-related factor 2 (TRF2)] or telomere-associated proteins [e.g., topoisomerase III (TOP3)] from their telomeric sites (12)(13)(14). TMS is proposed to compete with such proteins for binding to G4 DNA or stabilizing a G4 structure that is not favorably bound by the telomere-interacting protein, leading to telomere uncapping in cells with alternative lengthening of telomere (12,14).…”

Section: Synergistic Effect Of Nsc 19630 and Telomestatin On Cell Promentioning

confidence: 99%

“…TMS is proposed to compete with such proteins for binding to G4 DNA or stabilizing a G4 structure that is not favorably bound by the telomere-interacting protein, leading to telomere uncapping in cells with alternative lengthening of telomere (12,14). TMS also can reduce proliferation of telomerase-positive tumor cells effectively by inhibiting telomerase (13,15).…”

Section: Synergistic Effect Of Nsc 19630 and Telomestatin On Cell Promentioning

confidence: 99%

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Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress

Aggarwal

Sommers

Shoemaker

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

175

184

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Modulation of DNA repair proteins by small molecules has attracted great interest. An in vitro helicase activity screen was used to identify molecules that modulate DNA unwinding by Werner syndrome helicase (WRN), mutated in the premature aging disorder Werner syndrome. A small molecule from the National Cancer Institute Diversity Set designated NSC 19630 [1-(propoxymethyl)-maleimide] was identified that inhibited WRN helicase activity but did not affect other DNA helicases [Bloom syndrome (BLM), Fanconi anemia group J (FANCJ), RECQ1, RecQ, UvrD, or DnaB). Exposure of human cells to NSC 19630 dramatically impaired growth and proliferation, induced apoptosis in a WRN-dependent manner, and resulted in elevated γ-H2AX and proliferating cell nuclear antigen (PCNA) foci. NSC 19630 exposure led to delayed S-phase progression, consistent with the accumulation of stalled replication forks, and to DNA damage in a WRN-dependent manner. Exposure to NSC 19630 sensitized cancer cells to the G-quadruplex–binding compound telomestatin or a poly(ADP ribose) polymerase (PARP) inhibitor. Sublethal dosage of NSC 19630 and the chemotherapy drug topotecan acted synergistically to inhibit cell proliferation and induce DNA damage. The use of this WRN helicase inhibitor molecule may provide insight into the importance of WRN-mediated pathway(s) important for DNA repair and the replicational stress response.

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Section: Synergistic Effect Of Nsc 19630 and Telomestatin On Cell Promentioning

confidence: 99%

Section: Synergistic Effect Of Nsc 19630 and Telomestatin On Cell Promentioning

confidence: 99%

Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress

Aggarwal

Sommers

Shoemaker

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

175

184

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“…[18] Notably, in the latter case, although there are few doubts that this molecule stacks well on terminal G-quartets, no structural data is available besides a recent molecular-modeling study. [19] Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Recognition of G‐Quadruplex DNA by Triangular Star‐Shaped Compounds: With or Without Side Chains?

Bertrand

Granzhan

Monchaud

et al. 2011

Chemistry A European J

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We report the synthesis of two new series of triangular aromatic platforms, either with three aminoalkyl side chains (triazatrinaphthylene series, TrisK: six compounds), or without side chains (triazoniatrinaphthylene, TrisQ). The quadruplex-DNA binding behavior of the two series, which differ essentially by the localization of the cationic charges, was evaluated by means of FRET-melting and G4-FID assays. For the trisubstituted triazatrinaphthylenes (TrisK), the length of the substituents and the presence of terminal hydrogen-bond-donor groups (NH(2)) were shown to be crucial for ensuring a high quadruplex affinity (ΔT(1/2) values of up to 20 °C at 1 μM for the best candidate, TrisK3-NH) and selectivity versus duplex DNA. Subsequently, comparison of data collected on both the telomeric- and c-myc-quadruplex showed that the nonsubstituted TrisQ is even more efficient than TrisK3-NH, both in terms of quadruplex affinity (ΔT(1/2)=26 °C in K(+) buffer) and selectivity versus duplex DNA. Structural considerations conducted with the c-myc quadruplex indicate that both TrisK3-NH and TrisQ stack well onto the G-quartet but in an offset position, which might be influenced by the formation of multiple hydrogen bonds with the target in the former case. Finally, the nonsubstituted TrisQ displays a binding profile very similar to some of the best quadruplex binders, BRACO-19 and bisquinolinium 360A, used herein as references, and thereby represents a highly promising novel molecular design for quadruplex recognition.

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“…In our discovery of the first WRN helicase inhibitor (NSC 19630), we evaluated several DNA-interacting or damaging compounds as well as a DNA repair inhibitor for chemically induced synthetic lethality with NSC 19630 [10]. The first of these was telomestatin (TMS), a drug known to disrupt normal telomere capping and bind G-quadruplex (G4) DNA [25-27]. Previous work had implicated a role of WRN helicase to unwind DNA structure arising from the G-rich strand of the telomeric tail at the chromosome end [28].…”

Section: Research Strategies To Investigate Helicase Inhibitors Anmentioning

confidence: 99%

Biochemical and cell biological assays to identify and characterize DNA helicase inhibitors

Banerjee

Aggarwal

Sommers

et al. 2016

Methods

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The growing number of DNA helicases implicated in hereditary disorders and cancer indicates that this particular class of enzymes plays key roles in genomic stability and cellular homeostasis. Indeed, a large body of work has provided molecular and cellular evidence that helicases act upon a variety of nucleic acid substrates and interact with numerous proteins to enact their functions in replication, DNA repair, recombination, and transcription. Understanding how helicases operate in unique and overlapping pathways is a great challenge to researchers. In this review, we describe a series of experimental approaches and methodologies to identify and characterize DNA helicase inhibitors which collectively provide an alternative and useful strategy to explore their biological significance in cell-based systems. These procedures were used in the discovery of biologically active compounds that inhibited the DNA unwinding function catalyzed by the human WRN helicase-nuclease defective in the premature aging disorder Werner Syndrome. We describe in vitro and in vivo experimental approaches to characterize helicase inhibitors with WRN as the model, anticipating that these approaches may be extrapolated to other DNA helicases, particularly those implicated in DNA repair and/or the replication stress response.

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The G-Quadruplex Ligand Telomestatin Impairs Binding of Topoisomerase IIIα to G-Quadruplex-Forming Oligonucleotides and Uncaps Telomeres in ALT Cells

Cited by 66 publications

References 55 publications

Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress

Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress

Recognition of G‐Quadruplex DNA by Triangular Star‐Shaped Compounds: With or Without Side Chains?

Biochemical and cell biological assays to identify and characterize DNA helicase inhibitors

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