Document Type

Article

Publication Date

2-2026

Identifier

DOI: 10.1038/s44321-025-00352-x; PMCID: PMC12905269

Abstract

Ubiquitin E3 ligases play crucial roles in the DNA damage response (DDR) by modulating the turnover, localization, activation, and interactions of DDR and DNA replication proteins. We performed a CRISPR-Cas9 knockout screen focused on ubiquitin E3 ligases and related proteins with the DNA topoisomerase I inhibitor camptothecin. This led us to establish that MAEA, a core subunit of the CTLH E3 ligase complex, is a critical regulator of homologous recombination and the replication stress response. In tandem, we identified eight patients with variants in MAEA who present with a neurodevelopmental disorder that we term DIADEM (Developmental delay and Intellectual disability Associated with DEfects in MAEA). Analysis of patient-derived cell lines and mutation modeling reveal an underlying defect in HR-dependent DNA repair and replication fork restart and protection as a likely cause of disease. Mechanistically, we find that MAEA dysfunction hinders DNA repair by reducing the efficiency of RAD51 loading at sites of DNA damage, which we propose may contribute to the presentation of DIADEM by compromising genome integrity and cell division during development.

Journal Title

EMBO Mol Med

Volume

18

Issue

2

First Page

492

Last Page

513

MeSH Keywords

Humans; DNA Repair; Developmental Disabilities; DNA Replication; Ubiquitin-Protein Ligases; DNA Damage; Rad51 Recombinase; Homologous Recombination; Male

PubMed ID

41420108

Keywords

DNA Repair; DNA Replication; Neurodevelopmental Disorder; Ubiquitin

Comments

Grants and funding

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Publisher's Link: https://link.springer.com/article/10.1038/s44321-025-00352-x

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