G-Quadruplex Assembly by Ribosomal DNA: Emerging Roles in Disease Pathogenesis and Cancer Biology

Datta, Asoke G.; Pollock, Kevin J.; Kormuth, Karen A.; Brosh, Robert M.

doi:10.1159/000516394

Cited by 16 publications

(17 citation statements)

References 111 publications

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“…In our case, a, b, c = 3; N i = 1. Recent studies have shown that G4 structures not only destabilize the function of the genome, but may also contribute to the transcription regulation in rDNA and other regions of the genome [ 25 ]. Accordingly, it seems probable that G4 in the intact Q1 region should inhibit production of the pRNA transcript.…”

Section: Discussionmentioning

confidence: 99%

Variability of Human rDNA and Transcription Activity of the Ribosomal Genes

Chmúrčiaková

Smirnov

Kurfürst

et al. 2022

IJMS

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Human ribosomal DNA is represented by hundreds of repeats in each cell. Every repeat consists of two parts: a 13 kb long 47S DNA with genes encoding 18S, 5.8S, and 28S RNAs of ribosomal particles, and a 30 kb long intergenic spacer (IGS). Remarkably, transcription does not take place in all the repeats. The transcriptionally silent genes are characterized by the epigenetic marks of the inactive chromatin, including DNA hypermethylation of the promoter and adjacent areas. However, it is still unknown what causes the differentiation of the genes into active and silent. In this study, we examine whether this differentiation is related to the nucleotide sequence of IGS. We isolated ribosomal DNA from the nucleoli of human-derived HT1080 cells, and separated methylated and non-methylated DNA by chromatin immunoprecipitation. Then, we used PCR to amplify a 2 kb long region upstream of the transcription start and sequenced the product. We found that six SNVs and a series of short deletions in a region of simple repeats correlated with the DNA methylation status. These data indicate that variability of IGS sequence may initiate silencing of the ribosomal genes. Our study also suggests a number of pathways to this silencing that involve micro-RNAs and/or non-canonical DNA structures.

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Section: Discussionmentioning

confidence: 99%

Variability of Human rDNA and Transcription Activity of the Ribosomal Genes

Chmúrčiaková

Smirnov

Kurfürst

et al. 2022

IJMS

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“…An elegant review by Datta et al has nicely described the G-quadruplex biology in ribosomal DNA (rDNA). It has been demonstrated that G4 targeting in ribosomes and other loci play a vital role in regulation of biological processes and genomic stability and also provide a useful approach to combat with cancer ( Datta et al, 2021 ).…”

Section: G-quadruplex Structuresmentioning

confidence: 99%

Non-canonical DNA structures: Diversity and disease association

2022

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A complete understanding of DNA double-helical structure discovered by James Watson and Francis Crick in 1953, unveil the importance and significance of DNA. For the last seven decades, this has been a leading light in the course of the development of modern biology and biomedical science. Apart from the predominant B-form, experimental shreds of evidence have revealed the existence of a sequence-dependent structural diversity, unusual non-canonical structures like hairpin, cruciform, Z-DNA, multistranded structures such as DNA triplex, G-quadruplex, i-motif forms, etc. The diversity in the DNA structure depends on various factors such as base sequence, ions, superhelical stress, and ligands. In response to these various factors, the polymorphism of DNA regulates various genes via different processes like replication, transcription, translation, and recombination. However, altered levels of gene expression are associated with many human genetic diseases including neurological disorders and cancer. These non-B-DNA structures are expected to play a key role in determining genetic stability, DNA damage and repair etc. The present review is a modest attempt to summarize the available literature, illustrating the occurrence of non-canonical structures at the molecular level in response to the environment and interaction with ligands and proteins. This would provide an insight to understand the biological functions of these unusual DNA structures and their recognition as potential therapeutic targets for diverse genetic diseases.

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“…31−33 While indiscriminate damage to nuclear DNA results in genotoxicity and unwanted side effects, targeting the nucleolus may trigger cancer cell death more selectively while sparing normal cells. 27,30 Many chemotherapeutics derived from anthraquinones, 34 fluorenones, 35 acridines, 36 and other polyaromatic chromophores show a high affinity for G-quadruplexes. Among these is quarfloxin, a fluoroquinoline derivative that accumulates in the nucleolus, 27 as demonstrated in lung adenocarcinoma cells.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Another regulatory role of the G-quadruplex DNA may exist in the cell’s nucleolus, which is currently being pursued as a potential cellular target for anticancer therapeutics. − The nucleolus plays a central role in the production of ribosomal RNA (rRNA) to sustain ribosome biogenesis during aberrant cell growth and proliferation. Ribosome biogenesis is tightly regulated by many cell signaling pathways that converge on the RNA polymerase I complex (Pol I) .…”

Section: Introductionmentioning

confidence: 99%

“…The transcription of rDNA by Pol I is thought to be accompanied by the formation of G-quadruplex structures in the nontemplate strand. Because rDNA transcription is upregulated in transformed cells (as manifest by greatly enlarged nucleoli compared with normal cells), , inhibition of Pol I-mediated transcription by small molecules, such as G-quadruplex binders, represents an attractive therapeutic strategy. − While indiscriminate damage to nuclear DNA results in genotoxicity and unwanted side effects, targeting the nucleolus may trigger cancer cell death more selectively while sparing normal cells. , …”

Section: Introductionmentioning

confidence: 99%

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Computational and Experimental Characterization of rDNA and rRNA G-Quadruplexes

Green

Pickard

et al. 2022

J. Phys. Chem. B

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DNA G-quadruplexes in human telomeres and gene promoters are being extensively studied for their role in controlling the growth of cancer cells. G-quadruplexes have been unambiguously shown to exist both in vitro and in vivo, including in the guanine (G)-rich DNA genes encoding pre-ribosomal RNA (pre-rRNA), which is transcribed in the cell’s nucleolus. Recent studies strongly suggest that these DNA sequences (“rDNA”), and the transcribed rRNA, are a potential anticancer target through the inhibition of RNA polymerase I (Pol I) in ribosome biogenesis, but the structures of ribosomal G-quadruplexes at atomic resolution are unknown and very little biophysical characterization has been performed on them to date. In the present study, circular dichroism (CD) spectroscopy is used to show that two putative rDNA G-quadruplex sequences, NUC 19P and NUC 23P and their counterpart rRNAs, predominantly adopt parallel topologies, reminiscent of the analogous telomeric quadruplex structures. Based on this information, we modeled parallel topology atomistic structures of the putative ribosomal G-quadruplexes. We then validated and refined the modeled ribosomal G-quadruplex structures using all-atom molecular dynamics (MD) simulations with the CHARMM36 force field in the presence and absence of stabilizing K+. Motivated by preliminary MD simulations of the telomeric parallel G-quadruplex (TEL 24P) in which the K+ ion is expelled, we used updated CHARMM36 force field K+ parameters that were optimized, targeting the data from quantum mechanical calculations and the polarizable Drude model force field. In subsequent MD simulations with optimized CHARMM36 parameters, the K+ ions are predominantly in the G-quadruplex channel and the rDNA G-quadruplexes have more well-defined, predominantly parallel-topology structures as compared to rRNA. In addition, NUC 19P is more structured than NUC 23P, which contains extended loops. Results from this study set the structural foundation for understanding G-quadruplex functions and the design of novel chemotherapeutics against these nucleolar targets and can be readily extended to other DNA and RNA G-quadruplexes.

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G-Quadruplex Assembly by Ribosomal DNA: Emerging Roles in Disease Pathogenesis and Cancer Biology

Cited by 16 publications

References 111 publications

Variability of Human rDNA and Transcription Activity of the Ribosomal Genes

Variability of Human rDNA and Transcription Activity of the Ribosomal Genes

Non-canonical DNA structures: Diversity and disease association

Computational and Experimental Characterization of rDNA and rRNA G-Quadruplexes

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