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Potentiation by Protein Synthesis Inducers of Translational Readthrough of Pathogenic Premature Termination Codons in

Leire Torices1, Caroline E Nunes-Xavier1,2,3, Rafael Pulido1,3,4

  • 1Biobizkaia Health Research Institute, 48903 Barakaldo, Spain.

Cancers
|August 29, 2024
PubMed

Insights

Researchers found that specific drug combinations can restore the function of PTEN-L, a protein variant implicated in PTEN hamartoma tumor syndrome (PHTS). This approach targets premature termination codons (PTCs) to enable functional protein production.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • PTEN tumor suppressor is crucial, but mutations causing premature termination codons (PTCs) lead to non-functional proteins.
  • PTEN hamartoma tumor syndrome (PHTS) is linked to these PTEN-related genetic defects.
  • Previous work showed aminoglycosides can restore PTEN function by readthrough.

Purpose of the Study:

  • To investigate the functional readthrough of the PTEN-L isoform, which has PTCs in its N-terminal extension.
  • To understand how specific PTCs and surrounding sequences affect readthrough efficiency.
  • To explore strategies for enhancing PTEN protein reconstitution.

Main Methods:

  • Studied readthrough efficiency of PTEN-L variants with specific PTCs using aminoglycosides.
  • Analyzed the impact of nucleotide sequences proximal to PTCs.
  • Compared human and mouse PTEN PTC variants.
  • Investigated the correlation between protein synthesis levels and readthrough efficiency.
  • Tested combinations of aminoglycosides and protein synthesis inducers.

Main Results:

  • Achieved efficient functional readthrough of the PTEN-L isoform.
  • Identified specific PTCs and their sequences critical for optimal readthrough.
  • Demonstrated similar readthrough patterns for human and mouse PTEN PTC variants.
  • Found readthrough efficiency correlated with the amount of synthesized PTEN protein.
  • Combination therapy enhanced readthrough for certain PTEN PTCs.

Conclusions:

  • Drug-based readthrough can functionally restore PTEN-L, a relevant isoform in PHTS.
  • Optimizing readthrough requires understanding PTC context and enhancing protein synthesis.
  • This strategy offers potential for treating diseases caused by PTEN PTC variants.
Keywords:
PHTSgenetic diseaseprecision therapypremature termination codontranslational readthrough

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