Eukaryotic DNA replication requires the precise assembly of MCM2-7 single hexamers (SHs) into head-to-head double hexamers (DHs) at replication origins. While DH formation is well-characterized in budding yeast, the underlying mechanisms in human cells remain poorly understood. Here, we report cryo-electron microscopy structures of endogenous human MCM2-7 SH isolated from G1-phase cells. In these structures, human MCM2-7 adopts a latched spiral conformation in an autoinhibited state where the carboxyl-terminal extension (CTE) of MCM5 occupies the central channel, and MCM3-CTE is capable of locking the MCM2-5 gate to occlude DNA entry. Systematic functional analysis demonstrates that the six CTEs of MCM2-7 play distinct roles in SH stability, MCM loading, and DH formation on chromatin. Surprisingly, unlike in yeast, the human MCM3-CTE is dispensable for cell viability but ensures efficient genome-wide replication initiation. Our findings establish how human MCM2-7 enables flexible yet precise MCM loading via its CTEs, providing a framework for understanding the regulation of DNA replication initiation in higher eukaryotes.
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| Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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| Site | Modification | Modifier | Source | Reference |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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| Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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| Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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