RNA and DNA G-quadruplexes bind to human dicer and inhibit its activity

Koralewska, Natalia; Szczepańska, Agnieszka; Ciechanowska, Kinga; Wojnicka, Marta; Pokornowska, Maria; Milewski, Marek C.; Gudanis, Dorota; Baranowski, Daniel; Nithin, Chandran; Bujnicki, Janusz; Gdaniec, Zofia; Figlerowicz, Marek; Kurzyńska-Kokorniak, Anna

doi:10.1007/s00018-021-03795-w

Cited by 11 publications

(4 citation statements)

References 56 publications

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“…), cations (i.e., K + ), and small molecule ligands [205], making RG4s highly dynamic. Very recent data underline a regulatory function played by RG4 in miRNA maturation through DROSHA-and Dicer-inhibition [206] and a potential role in physiological and pathological LLPS [207,208]. The presence of the RG4 structure in pre-miRNA exists in equilibrium with the canonical stem-loop structures, and this equilibrium regulates the maturation of some miRNAs, such as miR-92b [209].…”

Section: Conclusive Remarks and Future Perspectivesmentioning

confidence: 99%

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Malfatti,

Bellina,

Antoniali

et al. 2023

Cells

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APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.

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Section: Conclusive Remarks and Future Perspectivesmentioning

confidence: 99%

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Malfatti,

Bellina,

Antoniali

et al. 2023

Cells

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“…All the studies indicate that rG4s in the pre-miRNAs compete with the stem-loop structures recognized by Dicer, thus inhibiting Dicer-mediated maturation and consequently reducing the mature miRNAs levels [26][27][28][29][30][31][32][33]. In addition, a recent report demonstrated that G4s bind to Dicer and inhibit its activity [34]. The formation and function of rG4s in mature miRNAs has been also reported in several works, suggesting a role in impairing miRNA binding to target mRNAs [35][36][37].…”

Section: Introductionmentioning

confidence: 74%

G-Quadruplexes Regulate miRNA Biogenesis in Live Zebrafish Embryos

Steeman

Weiner

David

et al. 2023

IJMS

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RNA guanine quadruplexes (G4s) regulate RNA functions, metabolism, and processing. G4s formed within precursors of microRNAs (pre-miRNAs) may impair pre-miRNAs maturation by Dicer, thus repressing mature miRNA biogenesis. As miRNAs are essential for proper embryonic development, we studied the role of G4s on miRNA biogenesis in vivo during zebrafish embryogenesis. We performed a computational analysis on zebrafish pre-miRNAs to find putative G4 forming sequences (PQSs). The precursor of the miRNA 150 (pre-miR-150) was found to contain an evolutionarily conserved PQS formed by three G-tetrads and able to fold in vitro as G4. MiR-150 controls the expression of myb, which shows a well-defined knock-down phenotype in zebrafish developing embryos. We microinjected zebrafish embryos with in vitro transcribed pre-miR-150 synthesized using either GTP (G-pre-miR-150) or 7-Deaza-GTP, a GTP analogue unable to form G4s (7DG-pre-miR-150). Compared to embryos injected with G-pre-miR-150, embryos injected with 7DG-pre-miR-150 showed higher levels of miRNA 150 (miR-150) and lower levels of myb mRNA and stronger phenotypes associated with myb knock-down. The incubation of pre-miR-150 prior to the injection with the G4 stabilizing ligand pyridostatin (PDS) reverted gene expression variations and rescued the phenotypes related to myb knock-down. Overall, results suggest that the G4 formed in pre-miR-150 functions in vivo as a conserved regulatory structure competing with the stem-loop structure necessary for miRNA biogenesis.

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“…Importantly, in a cell, ASOs can interact not only with RNAs (hybridization-dependent interactions) but also with proteins (hybridization-independent interactions), which may lead to unintended side effects ( 66 ). Considering Dicer, the results of our previous studies indicated that human Dicer is able to bind 14 nt oligomers and longer species ( 67 , 68 ). Additionally, oligonucleotides binding to Dicer have the potential to influence its pre-miRNA cleavage activity, acting as competitive or allosteric inhibitors ( 59 ).…”

Section: Resultsmentioning

confidence: 99%

Short 2′-O-methyl/LNA oligomers as highly-selective inhibitors of miRNA production in vitro and in vivo

Koralewska,

Corradi,

Milewski

et al. 2024

Nucleic Acids Research

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MicroRNAs (miRNAs) that share identical or near-identical sequences constitute miRNA families and are predicted to act redundantly. Yet recent evidence suggests that members of the same miRNA family with high sequence similarity might have different roles and that this functional divergence might be rooted in their precursors' sequence. Current knock-down strategies such as antisense oligonucleotides (ASOs) or miRNA sponges cannot distinguish between identical or near identical miRNAs originating from different precursors to allow exploring unique functions of these miRNAs. We here develop a novel strategy based on short 2′-OMe/LNA-modified oligonucleotides to selectively target specific precursor molecules and ablate the production of individual members of miRNA families in vitro and in vivo. Leveraging the highly conserved Xenopus miR-181a family as proof-of-concept, we demonstrate that 2′-OMe/LNA-ASOs targeting the apical region of pre-miRNAs achieve precursor-selective inhibition of mature miRNA-5p production. Furthermore, we extend the applicability of our approach to the human miR-16 family, illustrating its universality in targeting precursors generating identical miRNAs. Overall, our strategy enables efficient manipulation of miRNA expression, offering a powerful tool to dissect the functions of identical or highly similar miRNAs derived from different precursors within miRNA families.

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RNA and DNA G-quadruplexes bind to human dicer and inhibit its activity

Cited by 11 publications

References 56 publications

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

G-Quadruplexes Regulate miRNA Biogenesis in Live Zebrafish Embryos

Short 2′-O-methyl/LNA oligomers as highly-selective inhibitors of miRNA production in vitro and in vivo

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