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Related Concept Videos

Riboswitches01:56

Riboswitches

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Riboswitches are non-coding mRNA domains that regulate the transcription and translation of downstream genes without the help of proteins. Riboswitches bind directly to a metabolite and can form unique stem-loop or hairpin structures in response to the amount of the metabolite present. They have two distinct regions – a metabolite-binding aptamer and an expression platform.
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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After...
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Types of RNA01:20

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Three main types of RNA are involved in protein synthesis: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). These RNAs perform diverse functions and can be broadly classified as protein-coding or non-coding RNA. Non-coding RNAs play important roles in regulating gene expression in response to developmental and environmental changes. Non-coding RNAs in prokaryotes can be manipulated to develop more effective antibacterial drugs for human or animal use.
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Types of RNA01:23

Types of RNA

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Overview
Three main types of RNA are involved in protein synthesis: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). These RNAs perform diverse functions and can be broadly classified as protein-coding or non-coding RNA. Non-coding RNAs play important roles in the regulation of gene expression in response to developmental and environmental changes. Non-coding RNAs in prokaryotes can be manipulated to develop more effective antibacterial drugs for human or animal use.
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In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
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RNA functional modulation by Mitoxantrone via RNA structural ensemble repartitioning.

Chundan Zhang1, Ivana Borovská1,2, Teona Iobashvili1

  • 1Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, the Netherlands.

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This summary is machine-generated.

Small molecules can modulate gene expression by targeting RNA. The drug Mitoxantrone stabilizes RNA structures, altering gene translation and demonstrating a new strategy for targeting undruggable genes.

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Area of Science:

  • Molecular Biology
  • Chemical Biology
  • Drug Discovery

Background:

  • Small molecules offer a route to modulate gene expression, particularly at traditionally undruggable RNA targets.
  • Many RNAs exist as dynamic structural ensembles, presenting opportunities for modulation by small molecules.
  • Traditional screening methods often focus on stable RNA structures, limiting the scope of potential drug targets.

Purpose of the Study:

  • To explore the potential of small molecules in modulating RNA structure and function.
  • To identify specific small molecules that can repartition RNA conformational landscapes.
  • To investigate the mechanism by which small molecules interact with and alter RNA structures.

Main Methods:

  • Utilized group I self-splicing introns as a model system to identify RNA-binding small molecules.
  • Employed biochemical assays to determine the inhibitory concentration (IC50) of identified compounds.
  • Conducted transcriptome-wide chemical probing in human cells to map small molecule binding sites.
  • Analyzed alterations in RNA structural heterogeneity and translation in response to small molecule treatment.

Main Results:

  • Identified Mitoxantrone as a competitive inhibitor of RNA self-splicing, stabilizing the T4 td intron structure (IC50 = 4.3 μM).
  • Determined that the anthraquinone scaffold plus basic amine side chains are crucial for RNA structural modulation.
  • Observed preferential binding of Mitoxantrone to GC-rich structured regions in the transcriptome, with functional consequences in a subset.
  • Demonstrated that small molecules can alter the structural heterogeneity of 5' untranslated regions (UTRs), impacting translation.

Conclusions:

  • Small molecules can effectively repartition dynamic RNA conformational landscapes to modulate gene expression.
  • Mitoxantrone serves as a proof-of-concept for targeting RNA structure with small molecules, offering a strategy for previously undruggable targets.
  • Further exploration of small molecule-RNA interactions holds promise for novel therapeutic interventions.