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Related Concept Videos

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

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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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Ribosome Profiling02:24

Ribosome Profiling

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Ribosome profiling or ribo-sequencing is a deep sequencing technique that produces a snapshot of active translation in a cell. It selectively sequences the mRNAs protected by ribosomes to get an insight into a cell’s translation landscape at any given point in time.
Applications of ribosome profiling
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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.
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Alternative RNA Splicing02:18

Alternative RNA Splicing

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Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
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Regulation of Expression at Multiple Steps01:23

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

Wenjun Fan, Hester Liu, Gregory C Stachelek

    Biorxiv : the Preprint Server for Biology
    |August 30, 2024
    PubMed
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    Targeting ribosome production with RNA polymerase I (Pol I) inhibitors reveals a new cancer vulnerability. A specific mutation in RPL22 drives sensitivity to these drugs in microsatellite instable cancers.

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    Area of Science:

    • Molecular Biology
    • Cancer Biology
    • Genetics

    Background:

    • Ribosome biosynthesis is a critical process often exploited in cancer.
    • Targeting RNA polymerase I (Pol I) transcription is a strategy to inhibit ribosome production and combat cancer.
    • Understanding the molecular drivers of sensitivity to Pol I inhibitors is crucial for developing effective cancer therapies.

    Purpose of the Study:

    • To identify genetic drivers of sensitivity to Pol I inhibitors.
    • To elucidate the molecular mechanisms linking ribosome synthesis to cancer cell vulnerabilities.
    • To explore the interplay between RNA polymerase I activity and mRNA splicing.

    Main Methods:

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

    Main Results:

    • A frameshift mutation in ribosomal protein RPL22 was identified as a key driver of Pol I inhibitor sensitivity in microsatellite instable cancers.
    • RPL22 was found to directly interact with 28S rRNA and mRNA splice junctions, acting as a splicing regulator.
    • RPL22 deficiency, exacerbated by rRNA sequestration, promoted splicing of RPL22L1 and MDM4.
    • Inhibition of rRNA synthesis broadly altered mRNA splicing, affecting hundreds of targets.
    • RPL22-dependent alternative splicing changes were reversed by Pol I inhibition, indicating a tumor-suppressive pathway.

    Conclusions:

    • Ribosome biosynthesis is a cancer vulnerability linked to mRNA splicing regulation.
    • RPL22 plays a critical role in coordinating rRNA synthesis and mRNA splicing.
    • Pol I inhibition activates a ribotoxic stress response that impacts splicing and tumor suppression.