Spectroscopic analysis reveals the effect of hairpin loop formation on G-quadruplex structures

Feng, Hengxin; Kwok, Chun Kit

doi:10.1039/d2cb00045h

Cited by 4 publications

(3 citation statements)

References 28 publications

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“…In addition, peripheral nucleobases may be located at loops linking the G-tetrads among them or appear as ending groups . The latter were found to affect the fluorescence properties of G4 along with their topology or the type of the metal cations in their central cavity. ,− Another important structural characteristic of G4 is their molecularity . They may be formed by folding of a single, guanine-rich, DNA/RNA strand (monomolecular G4) or the association of two, three, or four strands, giving rise to bimolecular, trimolecular, or tetramolecular structures, respectively.…”

Section: Introductionmentioning

confidence: 99%

Fluorescence of Bimolecular Guanine Quadruplexes: From Femtoseconds to Nanoseconds

2022

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The paper deals with the fluorescence of guanine quadruplexes (G4) formed by association of two DNA strands d(GGGGTTTTGGGG) in the presence of K + cations, noted as OXY/K + in reference to the protozoon Oxytricha nova, whose telomere contains TTTTGGGG repeats. They were studied by steady-state and timeresolved techniques, time-correlated single photon counting, and fluorescence upconversion. The maximum of the OXY/K + fluorescence spectrum is located at 334 nm, and the quantum yield is 5.8 × 10 −4 . About 75% of the photons are emitted before 100 ps and stem from ππ* states, possibly with a small contribution of charge transfer. Time-resolved fluorescence anisotropy measurements indicate that ultrafast (<330 fs) excitation transfer, due to internal conversion among exciton states, is more efficient in OXY/K + compared to previously studied G4 structures. This is attributed to the arrangement of the peripheral thymines in two diagonal loops with restricted mobility, facilitating the interaction among them and with guanines. Thymines should also be responsible for a weak intensity excimer/exciplex emission band, peaking at 445 nm. Finally, the longest living fluorescence component (∼2.1 ns) is observed at the blue side of the spectrum. So far, high-energy long-lived emitting states had been reported only for double-stranded structures but not for G4.

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Section: Introductionmentioning

confidence: 99%

Fluorescence of Bimolecular Guanine Quadruplexes: From Femtoseconds to Nanoseconds

2022

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“…It discusses the reasons for which certain structural parameters (molecularity, topology, peripheral bases, and metal cations in the central cavity) affect, on the one hand, the fluorescence quantum yield Φ fl and the fluorescence spectral shape, and on the other, the photoionization quantum yield Φ i . Although similar questions have been addressed in phenomenological studies carried out by steady-state measurements, [31][32][33][34][35] the knowledge of the underlying primary processes offers a different perspective.…”

Section: Introductionmentioning

confidence: 98%

Processes triggered in guanine quadruplexes by direct absorption of UV radiation: From fundamental studies toward optoelectronic biosensors

Markovitsi

2023

Photochem & Photobiology

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Guanine quadruplexes (GQs) are four‐stranded DNA/RNA structures exhibiting an important polymorphism. During the past two decades, their study by time‐resolved spectroscopy, from femtoseconds to milliseconds, associated to computational methods, shed light on the primary processes occurring when they absorb UV radiation. Quite recently, their utilization in label‐free and dye‐free biosensors was explored by a few groups. In view of such developments, this review discusses the outcomes of the fundamental studies that could contribute to the design of future optoelectronic biosensors using fluorescence or charge carriers stemming directly from GQs, without mediation of other molecules, as it is the currently the case. It explains how the excited state relaxation influences both the fluorescence intensity and the efficiency of low‐energy photoionization, occurring via a complex mechanism. The corresponding quantum yields, determined with excitation at 266/267 nm, fall in the range of (3.0–9.5) × 10−4 and (3.2–9.2) × 10−3, respectively. These values, significantly higher than the corresponding values found for duplexes, depend strongly on certain structural factors (molecularity, metal cations, peripheral bases, number of tetrads …) which intervene in the relaxation process. Accordingly, these features can be tuned to optimize the desired signal.

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“…While most rG4s were canonical quadruplex structures (G 3–5 N 1–7 G 3–5 N 1–7 G 3–5 N 1–7 ), about 15% (595) of the rG4s were found to contain longer loops ( n > 7). For those long-loop rG4s, 39% had the potential to form duplex (or hairpin) structures by base pairing within loops, making their 3D structures distinct from simpler G4s. − Among the 230 putative hairpin-containing rG4 sequences corresponding to 72 genes (Supplementary File 1), a short RNA sequence from DHX15 mRNA was notable for three reasons. First, DHX15 protein is an RNA helicase involved in mRNA processing and immunity. , It has been reported that DHX15 is overexpressed in and leads to the progression of several cancer types, including prostate cancer, Burkitt lymphoma, and acute myeloid leukemia. − Second, as an RNA helicase, the DHX15 protein is difficult to target directly and selectively at the protein level with small molecules due to conserved nucleotide binding sites and complex ATP-dependent and -independent mechanisms. , No chemical inhibitors targeting this helicase have been published, and targeting the structured mRNA of DHX15 presents a potential path forward to targeting this disease-relevant gene that is complementary to targeting the protein itself.…”

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confidence: 99%

Competitive Microarray Screening Reveals Functional Ligands for the DHX15 RNA G-Quadruplex

Prestwood,

Yang,

Lewis

et al. 2024

ACS Med. Chem. Lett.

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RNAs are increasingly considered valuable therapeutic targets, and the development of methods to identify and validate both RNA targets and ligands is more important than ever. Here, we utilized a bioinformatic approach to identify a hairpincontaining RNA G-quadruplex (rG4) in the 5′ untranslated region (5′ UTR) of DHX15 mRNA. By using a novel competitive small molecule microarray (SMM) approach, we identified a compound that specifically binds to the DHX15 rG4 (K D = 12.6 ± 1.0 μM). This rG4 directly impacts translation of a DHX15 reporter mRNA in vitro, and binding of our compound (F1) to the structure inhibits translation up to 57% (IC 50 = 22.9 ± 3.8 μM). This methodology allowed us to identify and target the mRNA of a cancer-relevant helicase with no known inhibitors. Our target identification method and the novelty of our screening approach make our work informative for future development of novel small molecule cancer therapeutics for RNA targets.

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Spectroscopic analysis reveals the effect of hairpin loop formation on G-quadruplex structures

Abstract: This work studies the intrinsic fluorescence properties of long-loop G-quadruplexes (G4) with hairpin loop structures, revealing the unique information of G4 provided by intrinsic fluorescence compared to other spectroscopic assays.

Cited by 4 publications

References 28 publications

Fluorescence of Bimolecular Guanine Quadruplexes: From Femtoseconds to Nanoseconds

Fluorescence of Bimolecular Guanine Quadruplexes: From Femtoseconds to Nanoseconds

Processes triggered in guanine quadruplexes by direct absorption of UV radiation: From fundamental studies toward optoelectronic biosensors

Competitive Microarray Screening Reveals Functional Ligands for the DHX15 RNA G-Quadruplex

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