Show Notes
PNAS - This study identifies crotonylation as a posttranslational modification of c-Myc that reduces its transcriptional and oncogenic activity. Key lysines K289 and K298 are crotonylated; loss of crotonylation (including a cancer-derived K298N mutant) enhances Skp2 binding and tumorigenesis. Key terms: c-Myc, crotonylation, Skp2, posttranslational modification, oncogenesis.
Study Highlights:
The authors mapped ten crotonylated lysine residues on c-Myc and identified K289 and K298 as critical sites. Mutating these residues (2R or 8R mutants) increased c-Myc transcriptional activity, cell proliferation, colony formation, and promoter occupancy. Mechanistically, loss of crotonylation strengthened c-Myc binding to the E3 ligase Skp2 and reduced binding to p14ARF, linking crotonylation status to Skp2-mediated activation and turnover. A cancer-derived K298N mutation recapitulated enhanced transcriptional activity and produced larger xenograft tumors in mice.
Conclusion:
Crotonylation at specific C-terminal lysines restrains c-Myc oncogenic activity by limiting Skp2 interaction; disruption of this modification (including K298N) promotes transcriptional activation and tumor growth.
Music:
Enjoy the music based on this article at the end of the episode.
Article title:
Crotonylation impedes c-Myc oncogenic activity
Journal:
PNAS
DOI:
10.1073/pnas.2530020123
Reference:
https://doi.org/10.1073/pnas.2530020123
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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Episode link: https://basebybase.com/episodes/crotonylation-impedes-c-myc-activity
QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-09.
QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core scientific narrative: discovery of c-Myc crotonylation in human cells, identification of K289 and K298, mutational analyses (2R/8R), mechanistic link to Skp2 and transcriptional activation, in vivo K298N mutation and xenograft data, gut microbiota and crotonyl-CoA biology, and structural context via AlphaF
- transcript topics: c-Myc crotonylation in human cells; K289 and K298 crotonylation sites; crotonylation-deficient mutants 2R/8R and proliferation; Skp2 interaction and ARF competition; transcriptional activation and promoter occupancy; K298N cancer-derived mutant in vivo
QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0
Metadata Audited:
- article_doi
- article_title
- article_journal
- license
Factual Items Audited:
- c-Myc is crotonylated in human cells at K289 and K298.
- Crotonylation reduces binding of c-Myc to Skp2, dampening transcriptional activation.
- Crotonylation-deficient mutants (2R and 8R) increase cellular proliferation and colony formation across multiple cell lines.
- The cancer-derived K298N mutation shows increased transcriptional activity and oncogenic potential in vitro and in vivo.
- K289R and K298R substitutions abolish crotonylation at these sites and enhance Skp2 binding while reducing ARF interaction.
- AlphaFold predicts crotonylation drives a more compact, less disordered c-Myc conformation, impairing Skp2 binding.
QC result: Pass.
