Stress promotes RNA G-quadruplex folding in human cells

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 13, 2023

Guanine (G)-rich nucleic acids can fold into G-quadruplex (G4) structures under permissive conditions. Although many RNAs contain sequences that RNA G4s (rG4s) in vitro, their folding and functions vivo are not well understood. In this report, we showed the of putative rG4s human cells rG4 is dynamically regulated stress. By using high-throughput dimethylsulfate (DMS) probing, identified hundreds endogenous stress-induced rG4s, validated them by an pull-down approach. Our results demonstrate enriched mRNA 3'-untranslated regions enhance stability. Furthermore, readily reversible upon stress removal. summary, our study revealed dynamic regulation suggested widespread motifs may have a global regulatory impact on stability cellular response.

Язык: Английский

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Knot-knot chronicles: unveiling the G-quadruplexes

Critical Reviews in Biotechnology, Год журнала: 2025, Номер unknown, С. 1 - 16

Опубликована: Янв. 6, 2025

G-quadruplex structures (GQSes) are the intricate molecular knots or marvels that play diverse roles in various cellular processes, such as replication, transcription, and translation, which regulate gene expression. Even though GQSes can be found throughout genome, they more prevalent certain genomic regions like promoters 5'-UTRs. This review discusses functionality of across genome draws attention to intriguing world DNA RNA GQSes. We highlight uniqueness similarities RNA. The functional proteins interact with also discussed. In addition, role context plant development has been elaborated. approaches for detecting using different methods their influence regulating regulation described. provide insights into how used potential game changers biotechnology by utilizing them regulatory switches control aspects transcriptional post-transcriptional processes depending on arrangement

Язык: Английский

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How to untie G-quadruplex knots and why?

Cell chemical biology, Год журнала: 2021, Номер 28(4), С. 436 - 455

Опубликована: Фев. 17, 2021

Язык: Английский

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Beyond small molecules: targeting G-quadruplex structures with oligonucleotides and their analogues

Nucleic Acids Research, Год журнала: 2021, Номер 49(12), С. 6638 - 6659

Опубликована: Апрель 30, 2021

Abstract G-Quadruplexes (G4s) are widely studied secondary DNA/RNA structures, naturally occurring when G-rich sequences present. The strategic localization of G4s in genome areas crucial importance, such as proto-oncogenes and telomeres, entails fundamental implications terms gene expression regulation other important biological processes. Although thousands small molecules capable to induce G4 stabilization have been reported over the past 20 years, approaches based on hybridization a synthetic probe, allowing sequence-specific G4-recognition targeting still rather limited. In this review, after introducing general notions about G4s, we aim list, explain critically analyse more detail principal available target by using oligonucleotides analogues Locked Nucleic Acids (LNAs) Peptide (PNAs), reporting most relevant examples described literature date.

Язык: Английский

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On the Road to Fight Cancer: The Potential of G-Quadruplex Ligands as Novel Therapeutic Agents

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(11), С. 5947 - 5947

Опубликована: Май 31, 2021

Nucleic acid sequences able to adopt a G-quadruplex conformation are overrepresented within the human genome. This evidence strongly suggests that these genomic regions have been evolutionary selected play pivotal role in several aspects of cell biology. In present review article, we provide an overview on biological impact targeting G-quadruplexes cancer. A variety small molecules showing good stabilizing properties has reported exert antitumor activity preclinical models cancers. Moreover, promiscuous binders and multiple ligands, cancer defense responses synthetic lethal interactions also highlighted. Overall, gathered thus far indicates may represent innovative fascinating therapeutic approach for The continued methodological improvements, development specific tools careful consideration experimental settings living systems will be useful deepen our knowledge biology cancer, better define their as targets help design develop novel reliable G-quadruplex-based anticancer strategies.

Язык: Английский

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Biological relevance and therapeutic potential of G-quadruplex structures in the human noncoding transcriptome

Nucleic Acids Research, Год журнала: 2021, Номер 49(7), С. 3617 - 3633

Опубликована: Фев. 15, 2021

Abstract Noncoding RNAs are functional transcripts that not translated into proteins. They represent the largest portion of human transcriptome and have been shown to regulate gene expression networks in both physiological pathological cell conditions. Research this field has made remarkable progress comprehension how aberrations noncoding RNA drive relevant disease-associated phenotypes; however, biological role mechanism action several still need full understanding. Besides fulfilling its function through sequence-based mechanisms, can form complex secondary tertiary structures which allow non-canonical interactions with proteins and/or other nucleic acids. In context, presence G-quadruplexes microRNAs long is increasingly being reported. This evidence suggests a for controlling microRNA biogenesis mediating interaction partners, thus ultimately regulating expression. Here, we review state art transcriptome, their structural characterization. light existence further possible development G-quadruplex binders modulate conformation protein interactions, also discuss therapeutic potential as targets interfere RNAs.

Язык: Английский

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G4-quadruplex-binding proteins: review and insights into selectivity

Biophysical Reviews, Год журнала: 2022, Номер 14(3), С. 635 - 654

Опубликована: Апрель 20, 2022

There are over 700,000 putative G4-quadruplexes (G4Qs) in the human genome, found largely promoter regions, telomeres, and other regions of high regulation. Growing evidence links their presence to functionality various cellular processes, where proteins interact with them, either stabilizing and/or anchoring upon or unwinding them allow a process proceed. Interest understanding manipulating plethora processes regulated by these G4Qs has spawned new area small-molecule binder development, attempts mimic block associated G4-binding protein (G4BP). Despite growing interest focus on G4Qs, there is limited data (in particular, high-resolution structural information), nature G4Q-G4BP interactions what makes G4BP selective certain if fact they at all. This review summarizes current literature G4BPs regards providing groupings for binding mode, drawing conclusions around commonalities highlighting information specific available.

Язык: Английский

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G-Quadruplex-Binding Proteins: Promising Targets for Drug Design

Biomolecules, Год журнала: 2022, Номер 12(5), С. 648 - 648

Опубликована: Апрель 29, 2022

G-quadruplexes (G4s) are non-canonical secondary nucleic acid structures. Sequences with the potential to form G4s abundant in regulatory regions of genome including telomeres, promoters and 5′ non-coding regions, indicating they fulfill important functions. Generally, perform various biological functions by interacting proteins. In recent years, an increasing number G-quadruplex-binding proteins have been identified biochemical experiments. G4-binding involved vital cellular processes such as telomere maintenance, DNA replication, gene transcription, mRNA processing. Therefore, also associated human diseases. An intensive study G4-protein interactions provides attractive approach for therapeutics these can be considered drug targets novel medical treatment. this review, we present structural properties proteins, discuss how exploit develop new therapeutic targets.

Язык: Английский

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Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(2), С. 935 - 950

Опубликована: Янв. 6, 2022

The cationic porphyrin TMPyP4 is a well-established DNA G-quadruplex (G4) binding ligand that can stabilize different topologies via multiple modes. However, have both stabilizing and destabilizing effect on RNA G4 structures. structural mechanisms mediate unfolding remain unknown. Here, we report the TMPyP4-induced mechanism studied by well-tempered metadynamics (WT-MetaD) with supporting biophysical experiments. simulations predict two-state of interaction groove-bound top-face-bound conformation. dynamics stacking top tetrad disrupts Hoogsteen H-bonds between guanine bases, resulting in consecutive intercalation from top-to-bottom G-tetrads. results reveal striking correlation computational experimental approaches validate WT-MetaD as powerful tool for studying G4–ligand interactions.

Язык: Английский

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G-quadruplexes and associated proteins in aging and Alzheimer’s disease

Frontiers in Aging, Год журнала: 2023, Номер 4

Опубликована: Июнь 1, 2023

Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer’s disease (AD). characterized by progressive cognitive decline, memory loss, and neuropsychiatric behavioral symptoms, accounting most of the reported dementia cases. This now becoming major challenge burden on modern society, especially with aging population. Over last few decades, significant understanding pathophysiology AD has been gained studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, neuroinflammation. review focuses role non-canonical secondary structures DNA/RNA G-quadruplexes (G4s, G4-DNA, G4-RNA), G4-binding proteins (G4BPs), helicases, their roles in AD. Being critically important cellular function, G4s are involved regulation DNA RNA processes, replication, transcription, translation, localization, degradation. Recent studies have also highlighted G4-DNA’s inducing double-strand breaks that cause genomic instability G4-RNA’s participation regulating stress granule formation. emphasizes significance processes how homeostatic imbalance may contribute to

Язык: Английский

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