Self‐Splicing Group<scp>II</scp>Introns

Chillón, Isabel; Marcia, Marco

doi:10.1002/9783527814527.ch6

Cited by 4 publications

(3 citation statements)

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“…Splicing is a ubiquitous and essential biological reaction whereby protein-coding or regulatory RNAs (the exons) are excised from precursor transcripts by removing intronic sequences. In prokaryotes and eukaryotic organelles, splicing is performed by auto-catalytic introns, some of which regulate the expression of vital metabolic genes (Chillón I., 2021). Of these, the socalled group II introns constitute the ancestors of the eukaryotic spliceosome, a megadaltonlarge ribonucleoprotein complex that ensures the correct maturation of ~90% of human genes and whose aberrant activity causes ~15% of all human hereditary diseases and cancers (Jiang and Chen, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Besides catalyzing their self-splicing, group II introns also act as mobile retroelements, thus crucially contributing to genetic diversity throughout evolution (Martinez-Abarca and Toro, 2000). Importantly, as splicing ribozymes and retroelements, group II introns are potential targets of antifungal agents and molecular machines that can be engineered for site-specific insertion of cargo genes into genomic DNA (Chillón I., 2021). Therefore, their modulation with small RNA-targeting molecules has enormous potential to probe fundamental biological mechanisms, with direct translational applications in biotechnology and human medicine (Warner et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…During the first step of splicing, the 5'-exon is excised through a nucleophilic reaction that induces a transiently-inactive 'toggled' state, necessary to recruit the reactants of the second step (Manigrasso et al, 2020;Marcia and Pyle, 2012;Marcia et al, 2013b). Then, in the second step of splicing, the free 5′-exon attacks the 3′-splice junction, producing ligated exons and a free intron (Chillón I., 2021). This vital and multistep process involves sequence-specific interactions within a highly-structured metal-aided catalytic site, which in principle offers unique opportunities of favorable RNAligand interactions.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the conserved active site of splicing machines with specific and selective small molecule modulators

Silvestri

Manigrasso

Andreani

et al. 2023

Preprint

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The self-splicing group II introns are bacterial and organellar ancestors of the nuclear spliceosome and retro-transposable elements of pharmacological and biotechnological importance. Integrating enzymatic, crystallographic, and simulation studies, we demonstrate how these introns recognize small molecules through their conserved active site. These RNA-binding small molecules selectively inhibit the two steps of splicing by adopting distinctive poses at different stages of catalysis, and by preventing crucial active site conformational changes that are essential for splicing progression. Our data exemplify the enormous power of RNA binders to mechanistically probe vital cellular pathways. Most importantly, by proving that the evolutionarily-conserved RNA core of splicing machines can recognize small molecules specifically, our work puts solid bases for the rational design of splicing modulators not only against bacterial and organellar introns, but also against the human spliceosome, which is a validated drug target for the treatment of congenital diseases and cancers.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting the conserved active site of splicing machines with specific and selective small molecule modulators

Silvestri

Manigrasso

Andreani

et al. 2023

Preprint

Self Cite

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G·U base pairing motifs in long non-coding RNAs

2023

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On the Power and Challenges of Atomistic Molecular Dynamics to Investigate RNA Molecules

Muscat,

Martino,

Manigrasso

et al. 2024

J. Chem. Theory Comput.

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RNA molecules play a vital role in biological processes within the cell, with significant implications for science and medicine. Notably, the biological functions exerted by specific RNA molecules are often linked to the RNA conformational ensemble. However, the experimental characterization of such three-dimensional RNA structures is challenged by the structural heterogeneity of RNA and by its multiple dynamic interactions with binding partners such as small molecules, proteins, and metal ions. Consequently, our current understanding of the structure−function relationship of RNA molecules is still limited. In this context, we highlight molecular dynamics (MD) simulations as a powerful tool to complement experimental efforts on RNAs. Despite the recognized limitations of current force fields for RNA MD simulations, examining the dynamics of selected RNAs has provided valuable functional insights into their structures.

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Self‐Splicing GroupIIIntrons

Cited by 4 publications

References 138 publications

Targeting the conserved active site of splicing machines with specific and selective small molecule modulators

Targeting the conserved active site of splicing machines with specific and selective small molecule modulators

G·U base pairing motifs in long non-coding RNAs

On the Power and Challenges of Atomistic Molecular Dynamics to Investigate RNA Molecules

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