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Updated: Sep 8, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
A cancer-associated TP53 synonymous mutation induces synthesis of the p53 isoform p53/47
Rhythm Sajwan1, Lixiao Wang1, Olivera Casar-Borota2
1Department of Medical Biosciences, Umea University, Umea, Sweden.
Background:
Synonymous mutations (SMs) change the mRNA nucleotide sequences without altering the corresponding amino acid sequence and are usually overlooked due to their perceived lack of influence on protein function. However, emerging reports suggest that SMs play a significant role in disease development and progression.
Methods:
Whole exome sequencing, RNA-sequencing, and droplet digital PCR were performed to identify the SMs from the malignant glioma patients. MutaRNA was used to predict the effect of SMs on RNA structure in silico. SHAPE-MaP was performed to probe and assess the effect of SMs on RNA structure in-cellulo.
Results:
Here, we report that a Cancer-Associated SM in TP53 codon valine 203 (CASM203) results in the induction of the alternative translation initiated p53 protein isoform, p47. In-cell high-throughput RNA structural mapping showed that CASM203 mimics the Protein Kinase RNA-Like ER Kinase (PERK)-mediated p53 mRNA secondary structure that induces p47 expression of during the unfolded protein response (UPR).
Conclusions:
Overall, the single gain-of-function SM mimics the UPR-mediated p53 stress response, by generating RNA secondary structures akin to the PERK-mediated p53 mRNA structural switch. This illustrates the link between RNA structures and cellular biology and underscores the importance of SMs in cancer biology and their potential to further refine genetic diagnostics.
Insights
Synonymous mutations (SMs) can drive cancer by altering RNA structure. A specific SM in TP53 induces a p47 protein isoform, mimicking cellular stress responses and highlighting SMs
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Synonymous mutations (SMs) alter mRNA sequences without changing amino acids, often disregarded for their functional impact.
- Emerging evidence indicates SMs significantly contribute to disease development and progression, particularly in cancer.
Purpose of the Study:
- To investigate the functional consequences of SMs in malignant glioma.
- To explore the role of SMs in altering RNA structure and protein expression.
Main Methods:
- Whole exome sequencing, RNA-sequencing, and droplet digital PCR were employed to identify SMs in glioma patients.
- In silico prediction of SM effects on RNA structure using MutaRNA.
- In-cellulo assessment of SM-induced RNA structural changes via SHAPE-MaP.
Main Results:
- A cancer-associated SM in TP53 codon 203 (CASM203) was identified, leading to the induction of the p47 p53 protein isoform.
- CASM203 was shown to mimic the PERK-mediated p53 mRNA secondary structure.
- This mimicry induces p47 expression during the unfolded protein response (UPR).
Conclusions:
- A single gain-of-function SM can mimic UPR-mediated p53 stress responses by inducing specific RNA secondary structures.
- This study demonstrates a direct link between RNA structure, cellular biology, and cancer.
- SMs are crucial in cancer biology and offer potential for refining genetic diagnostics.
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