ArticleThe EMBO journal2024
Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins.
Article in The EMBO journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 9 citations in OpenAlex.
- USP1 inhibition promotes RAD18-dependent PCNA degradation and BRCA1 synthetic lethality.bioRxiv : the preprint server for biology · 2026Article
- Article
- Budding Yeast Ubiquitin Ligases Rad5 and Rad18 Bind a Novel PCNA Surface, which Is Required for their Functions in DNA-Damage Tolerance.International journal of biological sciences · 2026Article
- 101 Machine Learning Algorithms for Mining Esophageal Squamous Cell Carcinoma Neoantigen Prognostic Models in Single-Cell Data.International journal of molecular sciences · 2025Article
- Melanoma-associated antigen A4: A cancer/testis antigen as a target for adoptive T-cell receptor T-cell therapy.Cancer treatment reviews · 2025Review
- Long non-coding RNA MAGEA4-AS1 binding to p53 enhances MK2 signaling pathway and promotes the proliferation and metastasis of oral squamous cell carcinoma.Functional & integrative genomics · 2024Article
- Crystal structure of MAGEA4 MHD-RAD18 R6BD reveals a flipped binding mode compared to AlphaFold2 prediction.The EMBO journal · 2024Article
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8 authors at 2 institutions in 2 countries.
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Abstract
MAGEA4 is a cancer-testis antigen primarily expressed in the testes but aberrantly overexpressed in several cancers. MAGEA4 interacts with the RING ubiquitin ligase RAD18 and activates trans-lesion DNA synthesis (TLS), potentially favouring tumour evolution. Here, we employed NMR and AlphaFold2 (AF) to elucidate the interaction mode between RAD18 and MAGEA4, and reveal that the RAD6-binding domain (R6BD) of RAD18 occupies a groove in the C-terminal winged-helix subdomain of MAGEA4. We found that MAGEA4 partially displaces RAD6 from the RAD18 R6BD and inhibits degradative RAD18 autoubiquitination, which could be countered by a competing peptide of the RAD18 R6BD. AlphaFold2 and cross-linking mass spectrometry (XL-MS) also revealed an evolutionary invariant intramolecular interaction between the catalytic RING and the DNA-binding SAP domains of RAD18, which is essential for PCNA mono-ubiquitination. Using interaction proteomics, we found that another Type-I MAGE, MAGE-C2, interacts with the RING ubiquitin ligase TRIM28 in a manner similar to the MAGEA4/RAD18 complex, suggesting that the MAGEA4 peptide-binding groove also serves as a ligase-binding cleft in other type-I MAGEs. Our data provide new insights into the mechanism and regulation of RAD18-mediated PCNA mono-ubiquitination.
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