biostudies-literatureHough SHcambridgeuniversity | Cancer Research UK Cambridge Institute, University of CambridgeDeutsche Forschungsgemeinschaft (DFG)Cancer Research UKWeizmann Institute of ScienceIsraeli Council for Higher EducationWeizmann Institute of Science (WIS)Mark Foundation For Cancer Research (Mark Foundation)Deutsche ForschungsgemeinschaftEuropean Research CouncilMedical Research Councilcambridgeuniversity | Cancer Research UK Cambridge Institute, University of Cambridge (CRUK CI)Mark Foundation For Cancer ResearchWellcome TrustUKRI | Medical Research Council492-513https://www.ebi.ac.uk/biostudies/studies/S-EPMC12905269biostudies-literatureUnknown18(2)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 defecEMBO molecular medicineLoss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay.PMC12905269Outstanding Postdoctoral Women Fellowship393547839-SFB 1361ASPIRE II AwardKU 563/18-1855741 (DDREAMM)C6/A18796855741C17918/A28870C17918/A2887DRCPGM\100005SEBINT-2024/100003Postdoctoral Career Development AwardWT203144C17183/A23303C9545/A29580UKRI577227014/Z/23/Z206388/Z/17/ZJhujh SSMajumdar ADamseh NAwwad SWGiannini RBartik LStewart GSMosler TBelotserkovskaya RMcKee SCarnie CJSmedley DBader AZagnoli Vieira GColin EGalanty YJackson SPHough SHCacheiro PBeli PLewis OEThiffault ILam SSmerdon SJAmudhavalli SThomas JCClement EFluss JfalseLoss 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 defec2026-01-01T00:00:00Z2026 Feb2026-07-15T21:23:13.894Z2026-07-09T10:13:41.627ZS-EPMC129052694142010810.1038/s44321-025-00352-x