389: Crotonylation impedes c-Myc oncogenic activity

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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. 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, imp...