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Related Concept Videos

Transcriptional Regulation: Riboswitches01:23

Transcriptional Regulation: Riboswitches

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Riboswitches are RNA elements that regulate gene expression by altering their secondary structures in response to specific effector molecules. These elements, located in the leader regions of certain mRNAs, act as transcriptional regulators by toggling between alternative conformations to control downstream gene expression. Riboswitch-mediated regulation is a precise mechanism for modulating biosynthetic pathways, as exemplified by the riboflavin biosynthesis pathway in Bacillus...
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Ribosomal RNA Synthesis02:53

Ribosomal RNA Synthesis

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Ribosome synthesis is a highly complex and coordinated process involving more than 200 assembly factors. The synthesis and processing of ribosomal components occurs not only in the nucleolus but also in the nucleoplasm and the cytoplasm of eukaryotic cells.
Ribosome biogenesis begins with the synthesis of 5S and 45S pre-rRNAs by distinct RNA polymerases. The primary transcripts are extensively processed and modified before they are bound and folded by ribosomal proteins and assembly factors,...
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RNA Splicing01:32

RNA Splicing

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Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
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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.
The aptamer has high specificity for a particular metabolite which allows riboswitches to specifically regulate...
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Regulation of Expression at Multiple Steps01:23

Regulation of Expression at Multiple Steps

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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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Translational Regulation01:29

Translational Regulation

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Translational regulation in prokaryotes ensures efficient protein synthesis by controlling ribosome access to mRNA. This regulation is mediated by secondary RNA structures, including translational riboswitches, RNA thermometers, and small RNAs (sRNAs), which respond to intracellular and environmental signals to modulate gene expression.Translational RiboswitchesRiboswitches in the leader region of mRNAs can regulate translation by altering the accessibility of the Shine-Dalgarno (SD) sequence,...
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Updated: Sep 18, 2025

A Reporter Based Cellular Assay for Monitoring Splicing Efficiency
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Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22.

Wenjun Fan1, Hester Liu1, Gregory C Stachelek1

  • 1Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Cell Chemical Biology
|June 24, 2025
PubMed
Summary

Ribosome production is targeted in cancer. New drugs reveal RPL22 mutations drive sensitivity by altering RNA splicing, uncovering a novel tumor-suppressive pathway.

Keywords:
MDM4RPL22RPL22L1cancernucleolusrRNA synthesisribosome biogenesissmall-moleculesplicingtherapeutics

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Single Nucleotide Polymorphism-sensitive FISH Detection of Locus-specific Ribosomal RNA Transcription in Drosophila melanogaster
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Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Ribosome biosynthesis is a key vulnerability in cancer, targeted by inhibiting RNA polymerase I (Pol I) transcription.
  • Understanding the mechanisms of sensitivity to Pol I inhibitors is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To identify drivers of sensitivity to Pol I inhibitors.
  • To elucidate the mechanistic link between ribosome synthesis and mRNA splicing.
  • To uncover novel tumor suppressive pathways activated by Pol I inhibition.

Main Methods:

  • Integration of multi-omics and drug response data from a large cancer cell panel.
  • Development and application of specific Pol I inhibitors.
  • Analysis of protein-RNA interactions and mRNA splicing.
  • Genetic and chemical inhibition of rRNA synthesis.

Main Results:

  • RPL22 frameshift mutations were identified as conferring sensitivity to Pol I inhibitors.
  • RPL22 was found to directly interact with 28S rRNA and mRNA splice junctions, functioning as a splicing regulator.
  • RPL22 deficiency, exacerbated by 28S rRNA sequestration, promotes splicing of RPL22L1 and MDM4.
  • Inhibition of rRNA synthesis broadly remodels mRNA splicing, affecting hundreds of targets.
  • RPL22-dependent alternative splicing is reversed by Pol I inhibition, revealing a novel tumor suppressive pathway.

Conclusions:

  • A robust mechanism linking rRNA synthesis to mRNA splicing, coordinated by RPL22, has been uncovered.
  • Pol I inhibition activates a non-canonical ribotoxic stress pathway with tumor suppressive functions.
  • RPL22 mutations represent a potential biomarker for Pol I inhibitor sensitivity in cancer treatment.