Study reveals cryo-EM structures of human MCM2-7 in G1-phase, showing autoinhibited SHs forming latched spiral. Insight into DNA replication intricacies in human cells! PMID:42151158, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-73118-9 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪
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 p
