Suppressive cancer nonstop extension mutations increase C-terminal hydrophobicity and disrupt evolutionarily conserved amino acid patterns.
Humans
Hydrophobic and Hydrophilic Interactions
Neoplasms
/ genetics
Mutation
Amino Acids
/ metabolism
Smad4 Protein
/ genetics
MutL Protein Homolog 1
/ genetics
PTEN Phosphohydrolase
/ genetics
Evolution, Molecular
Codon, Terminator
/ genetics
Adenomatous Polyposis Coli Protein
/ genetics
Animals
Proteome
/ metabolism
Genes, Tumor Suppressor
Conserved Sequence
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 Oct 2024
25 Oct 2024
Historique:
received:
02
04
2024
accepted:
20
09
2024
medline:
25
10
2024
pubmed:
25
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39448564
doi: 10.1038/s41467-024-52779-4
pii: 10.1038/s41467-024-52779-4
doi:
Substances chimiques
Amino Acids
0
Smad4 Protein
0
MutL Protein Homolog 1
EC 3.6.1.3
MLH1 protein, human
0
PTEN Phosphohydrolase
EC 3.1.3.67
PTEN protein, human
EC 3.1.3.67
SMAD4 protein, human
0
Codon, Terminator
0
Adenomatous Polyposis Coli Protein
0
Proteome
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9209Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : Di 1421/9-2
Informations de copyright
© 2024. The Author(s).
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