Loss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay

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.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-12-19
DOI
https://doi.org/10.1038/s44321-025-00352-x
Primary Topic
DNA Repair Mechanisms
Type
article
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0.00
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article

Loss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay

Pilar Cacheiro, Damian Smedley, Petra Beli, Lauren Bartik et al.
EMBO Molecular Medicine
DNA Repair Mechanisms
article

Loss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay

Pilar Cacheiro, Damian Smedley, Petra Beli, Lauren Bartik, Aldo S. Bader, Isabelle Thiffault, Rimma Belotserkovskaya, Satpal S. Jhujh, Estelle Colin, Nadirah Damseh, Rosalinda Giannini, Thorsten Mosler, Samah W. Awwad, Soren Hough, Shivarajan Amudhavalli, Shane McKee, Guido Zagnoli-Vieira, Joël Fluss, Christopher J. Carnie, Grant S. Stewart, Stephen P. Jackson, Stephen J. Smerdon, Emma Clement, Yaron Galanty, John C. Thomas, Simon Lam, Anirban Majumdar, Oliver E Lewis
article en

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.

EMBO Molecular MedicineVol. 18(2)
Centre National de la Recherche Scientifique (FR), European Molecular Biology Organization (DE), Children's Mercy Hospital (US), University of Ulster (GB), Inserm (FR), Queen Mary University of London (GB), Johannes Gutenberg University Mainz (DE), Al-Quds University (PS), Heidelberg University (DE), University of Cambridge (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), Cancer Research UK (GB), The Gurdon Institute (GB), Bristol Royal Hospital for Children (GB), University Hospital Heidelberg (DE), Belfast City Hospital (GB), University Hospital of Geneva (CH), Centre Hospitalier Universitaire d'Angers (FR), Hopp Children's Cancer Center Heidelberg (DE), Mercy Hospital (US), European Molecular Biology Laboratory (DE), William Harvey Research Institute (GB), Institute of Molecular Biology (DE), Université d'Angers (FR), University of Missouri–Kansas City (US), University of Birmingham (GB)
Openalex Percentile: Top 62%
DNA Repair Mechanisms
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