biostudies-literatureYang RNIH NIGMSNational Institutes of HealthNIH NCI111100https://www.ebi.ac.uk/biostudies/studies/S-EPMC12830165biostudies-literatureUnknown302(2)Meier-Gorlin syndrome (MGS) is a form of primordial dwarfism linked to mutations in DNA replication initiation factors. Many MGS variants affect proteins required for the first step of replication initiation-the licensing of replication origins-during which the origin recognition complex (ORC), CDC6, and CDT1 cooperatively load MCM2-7 complexes onto DNA as an MCM double hexamer. The specific impacts of MGS mutations on origin licensing remain poorly understood. In this study, we systematically analyze the effects of MGS-linked missense mutations in core domains of human origin licensing factors in a fully reconstituted in vitro MCM loading system. Our results show that MGS mutations inhibit origin licensing by blocking MCM recruitment or loading at discrete but distinct stages of the reactThe Journal of biological chemistryMolecular impacts of Meier-Gorlin syndrome mutations on human origin licensing.PMC12830165R35GM158287R01-GM141313F31-CA278331Hunker OBleichert FYang RKim JfalseMolecular impacts of Meier-Gorlin syndrome mutations on human origin licensing.Meier-Gorlin syndrome (MGS) is a form of primordial dwarfism linked to mutations in DNA replication initiation factors. Many MGS variants affect proteins required for the first step of replication initiation-the licensing of replication origins-during which the origin recognition complex (ORC), CDC6, and CDT1 cooperatively load MCM2-7 complexes onto DNA as an MCM double hexamer. The specific impacts of MGS mutations on origin licensing remain poorly understood. In this study, we systematically analyze the effects of MGS-linked missense mutations in core domains of human origin licensing factors in a fully reconstituted in vitro MCM loading system. Our results show that MGS mutations inhibit origin licensing by blocking MCM recruitment or loading at discrete but distinct stages of the react2025-01-01T00:00:00Z2025 Dec2026-06-13T05:14:45.993Z2026-06-13T03:08:17.921ZS-EPMC128301654144843510.1016/j.jbc.2025.111100