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Suppressive cancer nonstop extension mutations increase C-terminal hydrophobicity and disrupt evolutionarily
Avantika Ghosh1,2, Marisa Riester1, Jagriti Pal1
1Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Abstract:
Nonstop extension mutations, a.k.a. stop-lost or stop-loss mutations, convert a stop codon into a sense codon resulting in translation into the 3' untranslated region until the next in-frame stop codon, thereby extending the C-terminus of a protein. In cancer, only nonstop mutations in SMAD4 have been functionally characterized, while the impact of other nonstop mutations remain unknown. Here, we exploit our pan-cancer NonStopDB dataset and test all 2335 C-terminal extensions arising from somatic nonstop mutations in cancer for their impact on protein expression. In a high-throughput screen, 56.1% of the extensions effectively reduce protein abundance. Extensions of multiple tumor suppressor genes like PTEN, APC, B2M, CASP8, CDKN1B and MLH1 are effective and validated for their suppressive impact. Importantly, the effective extensions possess a higher hydrophobicity than the neutral extensions linking C-terminal hydrophobicity with protein destabilization. Analyzing the proteomes of eleven different species reveals conserved patterns of amino acid distribution in the C-terminal regions of all proteins compared to the proteomes like an enrichment of lysine and arginine and a depletion of glycine, leucine, valine and isoleucine across species and kingdoms. These evolutionary selection patterns are disrupted in the cancer-derived effective nonstop extensions.
Insights
Nonstop extension mutations can decrease protein levels in cancer. These mutations impact tumor suppressor genes, and their effectiveness is linked to increased C-terminal hydrophobicity.
Area of Science:
- Genomics
- Proteomics
- Cancer Biology
Background:
- Nonstop extension mutations (stop-lost) create proteins with extended C-termini by altering stop codons.
- While SMAD4 nonstop mutations are known in cancer, the effects of others remain largely uncharacterized.
Purpose of the Study:
- To systematically evaluate the impact of 2335 somatic nonstop mutation-derived C-terminal extensions on protein expression across cancers.
- To identify characteristics of effective C-terminal extensions and their relationship to evolutionary patterns.
Main Methods:
- Utilized the pan-cancer NonStopDB dataset for analysis.
- Performed high-throughput screening to assess protein abundance changes.
- Analyzed C-terminal amino acid composition and hydrophobicity.
- Compared cancer-derived extensions with evolutionary conserved C-terminal patterns across species.
Main Results:
- 56.1% of C-terminal extensions significantly reduced protein abundance.
- Effective extensions were identified in tumor suppressor genes including PTEN, APC, B2M, CASP8, CDKN1B, and MLH1.
- Higher hydrophobicity correlated with effective protein destabilization.
- Cancer-derived extensions disrupted conserved evolutionary C-terminal amino acid distribution patterns.
Conclusions:
- Somatic nonstop mutations frequently lead to protein destabilization in cancer.
- C-terminal hydrophobicity is a key determinant of protein destabilization by these extensions.
- Disruption of evolutionary conserved C-terminal features by cancer mutations has functional consequences.
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