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S-CDK-regulated bipartite interaction of Mcm10 with MCM is essential for DNA replication

Xueting Wang1,2, Lu Liu3, Mengke Chen3

  • 1Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China.

Frontiers in Cell and Developmental Biology
|October 4, 2024
PubMed

Insights

Mcm10 phosphorylation by S-phase cyclin-dependent kinases enhances its association with MCM, crucial for DNA replication. This interaction is vital for cell cycle progression into S phase.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mcm10 is essential for activating the CMG replicative helicase via interaction with the MCM double hexamer.
  • This interaction is regulated throughout the cell cycle in Saccharomyces cerevisiae.

Purpose of the Study:

  • To investigate the role of Mcm10 phosphorylation at S66 by S-phase cyclin-dependent kinases (S-CDKs) in regulating Mcm10-MCM association.
  • To determine the functional significance of this interaction for DNA replication initiation.

Main Methods:

  • Site-directed mutagenesis (S66A) and N-terminal deletion of Mcm10.
  • Two-degron strategy for efficient Mcm10 depletion.
  • Complementation assays involving artificial tethering of Mcm10 mutants to MCM.

Main Results:

  • Phosphorylation of Mcm10 at S66 by S-CDKs enhances Mcm10-MCM association during S phase.
  • Mcm10 S66 phosphorylation is critical when the C-terminal MCM-binding domain is absent.
  • Mcm10-S66AΔC mutants exhibit severe S-phase entry defects and lethality, rescuable by tethering to MCM.

Conclusions:

  • Mcm10-MCM association is a tightly regulated, crucial event for DNA replication initiation.
  • S66 phosphorylation by S-CDKs serves as a key regulatory mechanism for Mcm10 function in S phase.
  • The study elucidates a critical checkpoint in DNA replication control.
Keywords:
DNA replicationMcm10cell cyclephosphorylationprotein–protein interaction

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