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Results for “Guanine quadruplex”

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PubMed2026

DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.

Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.

Humans↗

PubMed2026

Oxidative Damage Fine-Tunes G-Quadruplex Structures in Human Gene Promoters.

Oxidative damage can convert guanine (G) into 8-oxoguanine (O8G), resulting in altered gene expression and genome instability. However, the underlying molecular mechanisms remain poorly understood. Herein, we show that the NEIL3 gene proximal promoter sequence forms a mixture of parallel and hybrid G-quadruplex structures (NEIL3-G4s), exhibiting intrinsic structural polymorphism. Strikingly, site-specific O8G modifications significantly reduce this polymorphism, promoting the stabilization of either the parallel or the (3+1) hybrid-1 G4 topology. A single G-to-O8G substitution is sufficient to trigger a clear structural transition from the parallel to the (3+1) hybrid-1 G4, highlighting the profound impact of O8G on G4-mediated epigenetic regulation. We have determined the NMR solution structures of both native and O8G-modified NEIL3-G4s, providing mechanistic insights into how O8G induces specific G4 structural rearrangements. Functional analysis demonstrates that both forms of NEIL3-G4s can form in extended DNA contexts and inhibit DNA polymerase activity. Under oxidative stress, the formation of NEIL3-G4s correlates with elevated NEIL3 gene expression, suggesting that they play a role as sensors of oxidative damage and function as molecular switches for gene upregulation. Collectively, these findings underscore the crucial role of O8G-induced G4 structural plasticity in the cellular response to oxidative stress and in regulating gene expression.

G-Quadruplexes↗

PubMed2026

Unraveling G-Quadruplex and i-Motif Coexistence Within a Double-Stranded DNA.

DNA can transiently fold into variable arrangements, which are expected to exploit regulatory functions. Guanine-rich sequences can fold into G-quadruplexes (G4s), while the complementary strand adopts potentially i-Motif (iM) arrangements. Their concomitant formation at the same genomic site is still under debate. However, recently, single-molecule analyses have shown the simultaneous G4 and iM presence within a double-stranded (ds) DNA context, addressing them as synergic blockers of replication fork progression. While these findings point to a functional interplay between G4 and iM, a deeper understanding of the factors enabling their coexistence remains unclear. In this work, we unravel the equilibria governing G4- and iM-folding within dsDNA, adopting an extensive biophysical approach allowing analysis of an optimized modular system, scalable across constructs of increasing molecular complexity. Our findings corroborate the simultaneous formation model and further clarify the thermodynamic determinants driving duplex denaturation and the favorable folding of stable G4 and iM structures.

G-Quadruplexes↗

PubMed2025

G4STAB: a multi-input deep learning model to predict G-quadruplex thermodynamic stability based on sequence and salt concentration.

MOTIVATION: G-quadruplexes (G4s) are non-canonical nucleic acid structures formed in guanine-rich regions that modulate gene regulation and genomic stability. The thermodynamic stability of G4s directly influences their biological functions and potential as therapeutic targets. However, current quantitative frameworks for predicting G4 stability rely on predetermined structural features, limiting their effectiveness for diverse G4 topologies, and fail to account for environmental factors such as ion concentration and pH that significantly modulate G4 stability in cellular contexts. RESULTS: We present G4STAB, a multi-input deep learning neural network that accurately predicts DNA G4 melting temperatures based on sequence features, salt concentration, and pH. Trained on 2382 diverse DNA G4 sequences, our model achieves high accuracy (R 2=0.8) without relying on predetermined G4 structural features. G4STAB successfully captures established G4 stability determinants and proposes previously unobserved sequence-stability relationships. Analysis of 391 502 experimentally validated G4s reveals that cancer-like ionic environments alter G4 stability profiles, with a 13.5-fold increase in the number of structures exhibiting physiological melting temperatures (36-42°C). These findings suggest systematic genomic patterns in G4 stability responses across chromosomes and gene types. AVAILABILITY AND IMPLEMENTATION: G4STAB is available at https://github.com/donn-liew/G4STAB; G4STAB web database interface is available at https://donn-liew.github.io/g4stab-web-database/.

G-Quadruplexes↗

PubMed2026

Conservation of Long G4-rich (LG4) genomic enhancer regulations.

Long G4-rich regions (LG4s) are defined as DNA sequences containing a high density of guanine triplets capable of forming non-B DNA structures called G-quadruplexes (G4s). These regions frequently overlap with enhancers, which are regulatory DNA elements that modulate gene expression by interacting with DNA regions that dictate where transcription is initiated known as promoters. While LG4s have now been well-characterized in the human genome, neither LG4 occurrence, nor the ability of LG4s to function as enhancers, in other species has been described. To address this, we screened the genomes of 16 different species from various taxa to identify LG4s and then determined if they were conserved, and additionally, we show the ability of one of the conserved LG4s to interact with its cognate promoter in vitro is functionally maintained across species. Our analyses characterized a number of previously unreported LG4s in the human genome as well as LG4s in 13 additional species. Of note, we identified a highly conserved LG4 enhancer predicted to regulate over 40 genes. This LG4 is embedded in the MAZ (Myc-Associated Zinc finger protein) locus, and we find this LG4 possesses the ability to directly interact with the same target promoter in both human and mouse. In summary, this work describes LG4s in the genomes of both unicellular and multicellular species including vertebrates, invertebrates, plants, and fungi, and finds many of these LG4 sequences highly conserved.

G-Quadruplexes↗

PubMed2024

Viral hijacking of hnRNPH1 unveils a G-quadruplex-driven mechanism of stress control.

Viral genomes are enriched with G-quadruplexes (G4s), non-canonical structures formed in DNA or RNA upon assembly of four guanine stretches into stacked quartets. Because of their critical roles, G4s are potential antiviral targets, yet their function remains largely unknown. Here, we characterize the formation and functions of a conserved G4 within the polymerase coding region of orthoflaviviruses of the Flaviviridae family. Using yellow fever virus, we determine that this G4 promotes viral replication and suppresses host stress responses via interactions with hnRNPH1, a host nuclear protein involved in RNA processing. G4 binding to hnRNPH1 causes its cytoplasmic retention with subsequent impacts on G4-containing tRNA fragments (tiRNAs) involved in stress-mediated reductions in translation. As a result, these host stress responses and associated antiviral effects are impaired. These data reveal that the interplay between hnRNPH1 and both host and viral G4 targets controls the integrated stress response and viral replication.

Animals↗

PubMed2025

Viral hijacking of host DDX60 promotes Crimean-Congo haemorrhagic fever virus replication via G-quadruplex unwinding.

Crimean-Congo haemorrhagic fever virus (CCHFV) is the most prevalent tick-borne zoonotic bunyavirus, causing severe hemorrhagic fever and fatality in humans. Currently, the absence of approved vaccines or therapeutics for CCHFV infection necessitates the development of innovative therapeutic strategies. Here, we identify a guanine (G)-rich sequence located within the mRNA of the glycoprotein precursor in the medium (M) segment of the CCHFV genome, designated as M-PQS-1664(+). M-PQS-1664(+) can form stable G-quadruplex (G4) structure and functions as a negative regulatory element for viral replication. Host DDX60 is up-regulated in response to CCHFV infection, thereby it is hijacked to unwind M-PQS-1664(+) G4 for facilitating viral replication. The FDA-approved drug Cepharanthine (CEP), which competes with DDX60 to specifically stabilize M-PQS-1664(+) G4 without a global induction of host cellular G4s formation, exhibits remarkable antiviral activity in vitro and in vivo. More importantly, CEP possesses antiviral activity (50% inhibitory concentration ~ 0.2 μM) that having ~ 88 × the potency of ribavirin. Our findings underscore the CCHFV G4s as a promising target for drug development and highlight the significant potential of CEP in combating CCHFV.

Hemorrhagic Fever Virus, Crimean-Congo↗

PubMed2026

Structures and dynamics of the major G-quadruplex in the human PDGFR-β gene promoter: insights into vacancy G-quadruplex formation.

Overexpression of PDGFR-β (platelet-derived growth factor receptor beta) kinase contributes to diverse human diseases, including cancers, cardiovascular disorders, and fibrosis. G-quadruplexes (G4s) formed in the PDGFR-β promoter act as transcriptional repressors and represent attractive therapeutic targets. We previously reported that the major G4-forming region of the PDGFR-β promoter adopts a unique broken-strand G4, whereas truncation of this sequence generates a vacancy G4 (vG4) that can be filled-in by external guanine analogs or metabolites and further stabilized by small molecules, suggesting a potential regulatory mechanism and opportunity for selective drug targeting. However, the relationship between broken-strand G4s and vG4s remains unclear. Here, we demonstrate that the PDGFR-β promoter sequence forms a dynamic equilibrium between two broken-strand G4 conformations that interconvert on the millisecond timescale, with vG4 serving as an intermediate. We determined the high-resolution NMR structures of these interconverting G4s, which share a conserved vG4 core but differ in their intramolecular guanine "fill-in." Both conformations feature a stabilizing G-G capping base pair unique to the PDGFR-β promoter. These findings elucidate the structural details of broken-strand PDGFR-β promoter G4s and the mechanism of vG4 formation, providing critical insights for selective drug targeting and establishing a framework for rational design of small molecules to modulate PDGFR-β transcription.

G-Quadruplexes↗

PubMed2025

RNA G-quadruplexes emerge from a compacted coil-like ensemble via multiple pathways.

RNA G-quadruplexes (rG4s) are emerging as vital structural elements involved in processes like gene regulation, translation, and genome stability. Found in untranslated regions of messenger RNAs (mRNAs), they influence translation efficiency and mRNA localization. Additionally, rG4s of long noncoding RNAs and telomeric RNA play roles in RNA processing and cellular aging. Despite their significance, the atomic-level folding mechanisms of rG4s remain poorly understood due to their complexity. We studied the folding of the r(GGGA)3GGG and r(GGGUUA)3GGG (TERRA) sequences into parallel-stranded rG4 using all-atom enhanced-sampling molecular dynamics simulations, applying well-tempered metadynamics coupled with solute tempering. The obtained folding pathways suggest that RNA initially adopts a compacted coil-like ensemble characterized by dynamic guanine stacking and pairing. The three-quartet rG4 gradually forms from this compacted coil ensemble via diverse routes involving strand rearrangements and guanine incorporations. While the folding mechanism is multipathway, various two-quartet rG4 structures appear to be a common transitory ensemble along most routes. Thus, the process seems more complex than previously predicted, as G-hairpins or G-triplexes do not act as distinct intermediates, even though some are occasionally sampled. We also discuss the challenges of applying enhanced sampling methodologies to such a multidimensional free-energy surface and address the force-field limitations.

G-Quadruplexes↗