Related Experiment Video

Updated: Sep 27, 2025

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

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A Quality Control Mechanism of Splice Site Selection Abrogated under Stress and in Cancer

Maram Arafat1, Ruth Sperling1

  • 1Department of Genetics, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.

Cancers
|April 12, 2022
PubMed

Insights

Suppression of Splicing (SOS) prevents cells from using latent splice sites, but its failure in cancer generates faulty mRNAs. This mechanism, involving initiator-tRNA and nucleolin, offers new diagnostic and therapeutic targets for cancer.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Latent 5' splice sites are common in human introns but typically unused.
  • Suppression of Splicing (SOS) is a quality control mechanism preventing aberrant splicing.
  • SOS activation generates nonsense mRNAs and is independent of Nonsense-Mediated mRNA Decay (NMD).

Purpose of the Study:

  • To update the model of the SOS mechanism.
  • To investigate the role of initiator-tRNA and nucleolin in SOS.
  • To explore the implications of SOS abrogation in cancer.

Main Methods:

  • Investigated the role of initiator-tRNA in SOS.
  • Identified nucleolin as a nuclear binding partner of initiator-tRNA and a component of SOS.
  • Analyzed SOS abrogation and latent splicing activation in cancer cells (breast cancer, gliomas).

Main Results:

  • Initiator-tRNA plays a key role in SOS, independent of translation.
  • Nucleolin directly binds initiator-tRNA in the nucleus and is a protein component of SOS.
  • SOS is abrogated in cancer and under stress, leading to widespread latent splicing activation and thousands of nonsense mRNAs.
  • Latent splicing activation affects genes involved in cell proliferation and differentiation.
  • The extent of latent splicing activation correlates with cancer severity in oligodendroglioma.

Conclusions:

  • An updated SOS model includes nucleolin and initiator-tRNA.
  • Abrogation of SOS in cancer leads to aberrant mRNA isoforms with potential as diagnostic and therapeutic targets.
  • Latent splicing activation is a significant factor in cancer development and progression.
Keywords:
aberrant splicingalternative splicingbreast cancerendogenous spliceosomegliomalatent splicingpre-mRNA splicing

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