The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons

Moruno-Manchon, Jose F.; Koellhoffer, Edward C.; Gopakumar, Jayakrishnan; Hambarde, Shashank; Kim, Nayun; McCullough, Louise D.; Tsvetkov, Andrey S.

doi:10.18632/aging.101282

Cited by 66 publications

(68 citation statements)

References 54 publications

(72 reference statements)

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“…It has been demonstrated that the cationic porphyrin TMPyP4 and small molecule compound Pyridostatin (PDS) can bind to G-quadruplex strucures and either stabilize or destabilize them [ 17 , 66 , 67 ]. We performed CD melting experiments to determine melting temperatures (Tm) for Wt-KSHV-GQ and Wt-HCMV-GQ, respectively in the presence of TMPyP4 and PDS.…”

Section: Resultsmentioning

confidence: 99%

Analysis of G-quadruplexes upstream of herpesvirus miRNAs: evidence of G-quadruplex mediated regulation of KSHV miR-K12–1-9,11 cluster and HCMV miR-US33

Kumar

Choudhary

Patra

et al. 2020

BMC Mol and Cell Biol

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Background G-quadruplexes regulate gene expression, recombination, packaging and latency in herpesviruses. Herpesvirus-encoded miRNAs have been linked to important biological functions. The presence and the biological role of G-quadruplexes have not been studied in the regulatory regions of virus miRNA. We hypothesized that herpesvirus-encoded miRNAs are regulated by G-quadruplexes in their promoters. Results We analyzed the 1 kb regulatory regions of all herpesvirus-encoded miRNAs for the presence of putative quadruplex-forming sequences (PQS). Over two-third (67%) of the regulatory regions of herpesvirus miRNAs had atleast 1 PQS. The 200 bp region of the promoter proximal to herpesvirus miRNA is particularly enriched for PQS. We chose to study the G-quadruplex motifs in the promoters of miR-K12 cluster in Kaposi's sarcoma-associated Herpesvirus (KSHV miR-K12–1-9,11) and the miR-US33 encoded by Human Cytomegalovirus (HCMV miR-US33). Biophysical characterization indicates that the G-quadruplex motifs in the promoters of the KSHV miR-K12 cluster and the HCMV miR-US33 form stable intramolecular G-quadruplexes in vitro. Mutations disrupting the G-quadruplex motif in the promoter of the KSHV miR-K12 cluster significantly inhibits promoter activity, while those disrupting the motif in the promoter of HCMV miR-US33 significantly enhance the promoter activity as compared to that of the respective wild-type promoter. Similarly, the addition of G-quadruplex binding ligands resulted in the modulation of promoter activity of the wild-type promoters (with intact G-quadruplex) but not the mutant promoters (containing quadruplex-disrupting mutations). Conclusion Our findings highlight previously unknown mechanisms of regulation of virus-encoded miRNA and also shed light on new roles for G-quadruplexes in herpesvirus biology.

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Section: Resultsmentioning

confidence: 99%

Analysis of G-quadruplexes upstream of herpesvirus miRNAs: evidence of G-quadruplex mediated regulation of KSHV miR-K12–1-9,11 cluster and HCMV miR-US33

Kumar

Choudhary

Patra

et al. 2020

BMC Mol and Cell Biol

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“…The planar central moiety of BRACO‐19 can stack on the G‐quartet, binding through π–π interactions of the aromatic rings of the acridine and guanine molecules, while flanking groove binding arms enhance binding affinity (Burger et al, ; Sun et al, ). This overall small molecule architectural blueprint has led to a number of small molecules that have a great affinity for RNA and DNA GQs based on binding through planar stacking, intercalation and/or groove binding (Drygin et al, ; F. X. Han, Wheelhouse, & Hurley, ; H. Han, Cliff, & Hurley, ; Moruno‐Manchon et al, ). But still, very few small molecules have been found that can selectively bind to not only GQ‐based structures but selectively to the RNA product compared to the DNA.…”

Section: Targeting Rna G‐quadruplexes As a Therapeutic Approachmentioning

confidence: 99%

The role of RNA G‐quadruplexes in human diseases and therapeutic strategies

et al. 2019

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G-quadruplexes (GQs) are four-stranded secondary structures formed by G-rich nucleic acid sequence(s). DNA GQs are present abundantly in the genome and affect a wide range of processes associated with DNA. Recent studies show that RNA GQs are present in different transcripts, including coding and noncoding areas of mRNA, telomeric RNA as well as in other premature and mature noncoding RNAs. When present at specific locations within the RNAs, GQs play important roles in key biological functions, including the regulation of gene expression and telomere homeostasis. RNA GQs regulate pre-mRNA processing, such as splicing and polyadenylation. Evidently, among other processes, RNA GQs also control mRNA translation, miRNA and piRNA biogenesis, and RNA localization. The regulatory mechanisms controlled by RNA GQs mainly involve binding to RNA binding protein that modulate GQ conformation or serve as an entity in recruiting additional protein regulators to act as a block element to the processing machinery. Here we provide an overview of the ever-increasing number of discoveries revealing the role of RNA GQs in biology and their relevance in human diseases and therapeutics.

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“…Replication in yeast is impeded at G4 motifs when the G4 DNA helicase Pif1 is disrupted [63,79,80]. G4 DNA stabilized by small molecule ligands such as pyridostatin (PDS) or PhenDC3 increase the instability at G4-forming sequences in the eukaryotic genomes indicating that the stability of G4 DNA correlates with its efficacy as replication block [81][82][83][84]. Similarly, a more problematic obstacle to replication is expected when G4 DNA is in complex with high-affinity binding protein such as the Top1 catalytic mutant (Top1Y727F), which binds to G4 DNA to form a stable complex (Figure 1, Table 1).…”

Section: Dna-protein Complexes As Dna Replication Barriersmentioning

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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The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons

Cited by 66 publications

References 54 publications

Analysis of G-quadruplexes upstream of herpesvirus miRNAs: evidence of G-quadruplex mediated regulation of KSHV miR-K12–1-9,11 cluster and HCMV miR-US33

Analysis of G-quadruplexes upstream of herpesvirus miRNAs: evidence of G-quadruplex mediated regulation of KSHV miR-K12–1-9,11 cluster and HCMV miR-US33

The role of RNA G‐quadruplexes in human diseases and therapeutic strategies

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

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