Abstract 1185: Phosphorylation of the MYC oncoprotein disrupts the direct interaction of MYC with the ASF1A histone chaperone
Notice bibliographique
Résumé
Despite the profound role of deregulated MYC activity as a potent cancer driver, targeting MYC directly for the development of effective anti-cancer agents has not yet been fruitful. An alternate strategy is to disrupt the interaction of MYC with key partner proteins critical to MYC-driven oncogenesis. To this end, we took a triangulated strategy. First, we identified hundreds of direct and indirect MYC protein-protein interactions within cells using MYC-BioID mass spectrometry. Next to distinguish MYC-protein interactors that are functionally important for MYC oncogenic activity we performed a genome-wide CRISPR knock-out screen using an isogenic pair of normal and MYC-driven breast cancer cells. Finally, we distinguished key control points of MYC oncogenic activity and then identified protein that bound directly at these sites. This triangulated strategy has been highly fruitful. In this study, we focused on MYC phosphorylation as a key control point, as 20% of MYC is composed of residues with the potential to be phosphorylated, including Serine (S), Threonine, and Tyrosine. We have identified two regulatory phosphorylation sites, S71 and S81, that control MYC oncogenesis. Mutating each individual residue to alanine had no effect, however mutating both residues to alanine, resulted in a MYC protein that is gain-of-function (GoF) for MYC-driven transformation. To investigate the mechanism by which this GoF mutation results in potentiated oncogenic activity, we identified MYC protein-protein interactors controlled by MYC phosphorylation at these sites using our proximity-based labeling technique, BioID. We validated that the interaction of MYC with the histone chaperone ASF1A significantly increases with this MYC GoF protein within cells. The interaction is disrupted in response to MYC phosphorylation at these residues following Jun kinase activation under stressful conditions. This reinforces phosphorylation functions as a switch mechanism to inhibit MYC activity by disrupting MYC-ASF1A interaction. ASF1A binds to all variants of histone H3, functioning as an intermediary between several complexes responsible for the deposition of H3 variants in differing contexts associated with chromatin remodeling complexes, such as CAF-1 (RBBP4/CHAF1A/CHAF1B) and HIRA/UBN1/CABIN1. Interestingly, many of these complex components were hits in our CRISPR screen, further reinforcing functional relevance. Using NMR spectroscopy and biolayer interferometry, we have shown that MYC interacts directly with ASF1A. Moreover, this interaction of MYC-ASF1A is robustly abrogated by phosphomimetic mutations of either S71 or S81. Thus, we propose a model whereby phosphorylation of MYC at S71 and S81 blocks association with ASF1A. Due to its key role in replication and transcription, disrupting the MYC-ASF1A interaction has potential as a novel target for the development of anti-MYC therapeutics. Citation Format: Linda Z. Penn, Alannah MacDonald, Tristan Kenney, Adelaide Mitchell, Brian Raught, Cheryl Arrowsmith. Phosphorylation of the MYC oncoprotein disrupts the direct interaction of MYC with the ASF1A histone chaperone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1185.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».