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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
TP53 cancerous mutations exhibit selection for translation efficiency
Yedael Y Waldman1, Tamir Tuller, Roded Sharan
1Department of Molecular Microbiology and Biotechnology, Blavatnik School of Computer Science, Tel Aviv University, Ramat Aviv, Israel.
Abstract:
The tumor suppressor gene TP53 is known to be a key regulator in cancer, and more than half of human cancers exhibit mutations in this gene. Recent evidence shows that point mutations in TP53 not only disrupt its function but also possess gain-of-function and dominant-negative effects on wild-type copies, thus making the mutated gene an oncogene. Hence, this brings about the possibility that TP53 mutations may be under selection for increasing the overall translation efficiency (TE) of defected TP53 in cancerous cells. Here, we perform the first large-scale analysis of TE in human cancer mutated TP53 variants, identifying a significant increase in TE that is correlated with the frequency of TP53 mutations. Furthermore, mutations with a known oncogenic effect significantly increase their TE compared with the other TP53 mutations. Further analysis shows that TE may have influence both on selecting the location of the mutation and on its outcome: codons with lower TE show stronger selection toward nonsynonymous mutations and, for each codon, frequent mutations show stronger increase in TE compared with less frequent mutations. Additionally, we find that TP53 mutations have significantly higher TE increase in progressive versus primary tumors. Finally, an analysis of TP53 NCI-60 cell lines points to a coadaptation between the mutations and the tRNA pool, increasing the overall TP53 TE. Taken together, these results show that TE plays an important role in the selection of TP53 cancerous mutations.
Insights
TP53 mutations, common in cancer, may be selected to increase translation efficiency (TE). This study reveals increased TE in mutated TP53, correlating with mutation frequency and oncogenic effects, suggesting TE influences cancer development.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The TP53 gene is a critical tumor suppressor, frequently mutated in human cancers.
- TP53 mutations can gain oncogenic functions, including dominant-negative effects on wild-type TP53.
- Selection pressures may favor TP53 mutations that enhance translation efficiency (TE) in cancer cells.
Purpose of the Study:
- To investigate the role of translation efficiency (TE) in the selection of TP53 mutations during cancer development.
- To analyze the correlation between TE and the frequency and oncogenic effects of TP53 mutations.
- To explore how TE influences mutation location, outcome, and progression.
Main Methods:
- Large-scale analysis of TE in human cancer mutated TP53 variants.
- Correlation analysis between TE and TP53 mutation frequency and known oncogenic effects.
- Investigation of codon-specific TE and selection pressures.
- Comparison of TE increase in progressive versus primary tumors.
- Analysis of TP53 NCI-60 cell lines for coadaptation with tRNA pools.
Main Results:
- A significant increase in TE was identified in mutated TP53 variants, correlating with mutation frequency.
- TP53 mutations with known oncogenic effects showed significantly higher TE increases.
- Codons with lower TE exhibited stronger selection for nonsynonymous mutations.
- Frequent mutations demonstrated a greater TE increase compared to less frequent ones.
- Progressive tumors showed a higher TE increase in TP53 mutations than primary tumors.
- Evidence of coadaptation between TP53 mutations and tRNA pools was observed, enhancing overall TE.
Conclusions:
- Translation efficiency (TE) plays a significant role in the selection of TP53 mutations in cancer.
- TE influences the location and functional outcome of TP53 mutations.
- The findings suggest TE is a crucial factor in oncogenesis driven by TP53 mutations.
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