G-quadruplexes Mark Sites of Methylation Instability Associated with Ageing and Cancer

Rauchhaus, Jonas; Robinson, Jenna; Monti, Ludovica; Antonio, Marco Di

doi:10.3390/genes13091665

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…Nevertheless, as anticipated, Raucchaus et al reported that G4s are also highly present in terms of human aging clock sites. Most importantly, the authors highlighted the comparable enrichment of G4s in the binding sites of enzymes that operate both methylation and demethylation; this supports the hypothesis that G4s may be more involved in the perturbation of DNA-methylation than in the process that promotes either hyper-or hypomethylation [48]. Similarly, Moruno-Manchon et al showed that older mice treated with G4 binders (Figure 4a,b) had enhanced senescence-associated phenotypes in their brains, and they exhibited increased cognitive deficits.…”

Section: G-quadruplexes and Dna Methylationmentioning

confidence: 52%

“…G4s can be recognized by specific proteins, including methylation-regulating enzymes [47]. As anticipated, the DNA methylation level is one of the main biological clocks that indicate the extent of aging [19], and recent reports have noted the connection between G4s and aging; this is because sites that are considered to be aging clocks are enriched with G4-forming sequences [48].…”

Section: G-quadruplexes and Dna Methylationmentioning

confidence: 87%

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An Updated Overview on the Role of Small Molecules and Natural Compounds in the “Young Science” of Rejuvenation

Ribaudo

Gianoncelli

2023

Antioxidants

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Aging is a gradual process that occurs over time which leads to a progressive decline of cells and tissues. Telomere shortening, genetic instability, epigenetic alteration, and the accumulation of misfolded proteins represent the main hallmarks that cause perturbed cellular functions; this occurs in conjunction with the progression of the so-called “aging clocks”. Rejuvenation aims to influence the natural evolution of such aging clocks and to enhance regenerative capacity, thus overcoming the limitations of common anti-aging interventions. Current rejuvenation processes are based on heterochronic parabiosis, cell damage dilution through asymmetrical cell division, the excretion of extracellular vesicles, the modulation of genetic instability involving G-quadruplexes and DNA methylation, and cell reprogramming using Yamanaka factors and the actions of antioxidant species. In this context, we reviewed the most recent contributions that report on small molecules acting as senotherapeutics; these molecules act by promoting one or more of the abovementioned processes. Candidate drugs and natural compounds that are being studied as potential rejuvenation therapies act by interfering with CDGSH iron-sulfur domain 2 (CISD2) expression, G-quadruplex structures, DNA methylation, and mitochondrial decay. Moreover, direct and indirect antioxidants have been reported to counteract or revert aging through a combination of mixed mechanisms.

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Section: G-quadruplexes and Dna Methylationmentioning

confidence: 52%

Section: G-quadruplexes and Dna Methylationmentioning

confidence: 87%

An Updated Overview on the Role of Small Molecules and Natural Compounds in the “Young Science” of Rejuvenation

Ribaudo

Gianoncelli

2023

Antioxidants

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“…However, there are only a few studies on the involvement of G4 structures in the functioning of DNA methylation machinery [ 13 , 20 ]. Nevertheless, studies based on whole-genome sequencing data identified a correlation between CpG methylation levels and G4 formation, namely, hypomethylation of the genome in regions enriched in G4 motifs [ 21 , 22 ]. The G4 formation in the promoters of imprinted genes was revealed [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between G-Quadruplexes and Dnmt3a-Mediated Methylation of the c-MYC Oncogene Promoter

Sergeev,

Loiko,

Genatullina

et al. 2023

IJMS

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The methylation of cytosines at CpG sites in DNA, carried out de novo by DNA methyltransferase Dnmt3a, is a basic epigenetic modification involved in gene regulation and genome stability. Aberrant CpG methylation in gene promoters leads to oncogenesis. In oncogene promoters, CpG sites often colocalize with guanine-rich sequences capable of folding into G-quadruplexes (G4s). Our in vitro study aimed to investigate how parallel G4s formed by a sequence derived from the c-MYC oncogene promoter region affect the activity of the Dnmt3a catalytic domain (Dnmt3a-CD). For this purpose, we designed synthetic oligonucleotide constructs: a c-MYC G4-forming oligonucleotide and linear double-stranded DNA containing an embedded stable extrahelical c-MYC G4. The topology and thermal stability of G4 structures in these DNA models were analyzed using physicochemical techniques. We showed that Dnmt3a-CD specifically binds to an oligonucleotide containing c-MYC G4, resulting in inhibition of its methylation activity. c-MYC G4 formation in a double-stranded context significantly reduces Dnmt3a-CD-induced methylation of a CpG site located in close proximity to the quadruplex structure; this effect depends on the distance between the non-canonical structure and the specific CpG site. One would expect DNA hypomethylation near the G4 structure, while regions distant from this non-canonical form would maintain a regular pattern of high methylation levels. We hypothesize that the G4 structure sequesters the Dnmt3a-CD and impedes its proper binding to B-DNA, resulting in hypomethylation and activation of c-MYC transcription.

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“… 17 Moreover, some G4s are associated with DNA methylation instability, leading to aging and cancer, which increases the potential utility of these structures in clinical studies. 18 …”

Section: Introductionmentioning

confidence: 99%

Toward a Better Understanding of G4 Evolution in the 3 Living Kingdoms

Vannutelli,

Ouangraoua,

Perreault

2023

Evol Bioinform Online

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Background: G-quadruplexes (G4s) are secondary structures in DNA and RNA that impact various cellular processes, such as transcription, splicing, and translation. Due to their numerous functions, G4s are involved in many diseases, making their study important. Yet, G4s evolution remains largely unknown, due to their low sequence similarity and the poor quality of their sequence alignments across several species. To address this, we designed a strategy that avoids direct G4s alignment to study G4s evolution in the 3 species kingdoms. We also explored the coevolution between RBPs and G4s. Methods: We retrieved one-to-one orthologous genes from the Ensembl Compara database and computed groups of one-to-one orthologous genes. For each group, we aligned gene sequences and identified G4 families as groups of overlapping G4s in the alignment. We analyzed these G4 families using Count, a tool to infer feature evolution into a gene or a species tree. Additionally, we utilized these G4 families to predict G4s by homology. To establish a control dataset, we performed mono-, di- and tri-nucleotide shuffling. Results: Only a few conserved G4s occur among all living kingdoms. In eukaryotes, G4s exhibit slight conservation among vertebrates, and few are conserved between plants. In archaea and bacteria, at most, only 2 G4s are common. The G4 homology-based prediction increases the number of conserved G4s in common ancestors. The coevolution between RNA-binding proteins and G4s was investigated and revealed a modest impact of RNA-binding proteins evolution on G4 evolution. However, the details of this relationship remain unclear. Conclusion: Even if G4 evolution still eludes us, the present study provides key information to compute groups of homologous G4 and to reveal the evolution history of G4 families.

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G-quadruplexes Mark Sites of Methylation Instability Associated with Ageing and Cancer

Cited by 7 publications

References 29 publications

An Updated Overview on the Role of Small Molecules and Natural Compounds in the “Young Science” of Rejuvenation

An Updated Overview on the Role of Small Molecules and Natural Compounds in the “Young Science” of Rejuvenation

Crosstalk between G-Quadruplexes and Dnmt3a-Mediated Methylation of the c-MYC Oncogene Promoter

Toward a Better Understanding of G4 Evolution in the 3 Living Kingdoms

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