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<p>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.</p>

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Distinct roles of MCM2-7 subunits in replication licensing in human cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Xinyu Fan,
  • Wai Hei Lam,
  • Daqi Yu,
  • Huadong Jiang,
  • Yan Chit Hui,
  • Qiongdan Zhang,
  • Weiran Li,
  • Jian Li,
  • Ziyang Lin,
  • Zhan Yin,
  • Wenxiong Wu,
  • Yingyi Zhang,
  • Nan Liu,
  • Masato T. Kanemaki,
  • Shangyu Dang,
  • Yuanliang Zhai

摘要

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.