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MCM5 UFMylation regulates replication origin firing and fork progression.

Zheng Li1,2, Xingxuan Wu1,3, Liu Liu4

  • 1Guangdong Key Laboratory for Genome Stability & Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, China.

The EMBO Journal
|September 12, 2025
PubMed
Summary

UFMylation is crucial for cell proliferation by regulating DNA replication. This study shows UFM1 modification of MCM5 is essential for DNA replication, preventing microcephalic primordial dwarfism disorders.

Keywords:
CMG HelicaseDNA ReplicationOrigin FiringUFL1UFMylation

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • UFMylation is vital for cell proliferation, but its mechanism remains unclear.
  • Mutations in UFMylation pathway genes are linked to microcephalic primordial dwarfism (MPD).
  • MPD-associated mutations are found in DNA helicase complex components, including the MCM hexamer.

Purpose of the Study:

  • To elucidate the role of UFMylation in DNA replication.
  • To investigate the mechanistic link between UFMylation, DNA replication, and MPD disorders.

Main Methods:

  • Investigated UFMylation's effect on DNA replication using MPD-associated mutants.
  • Identified and characterized the UFMylation of MCM5 by the UFM1 E3 ligase UFL1.
  • Analyzed the impact of Lys583 UFMylation on MCM5 and the CMG helicase complex stability.

Main Results:

  • All tested MPD-associated mutations in UFMylation enzymes impaired DNA replication.
  • UFL1 catalyzes Lys583 UFMylation of MCM5, a key part of the CMG helicase.
  • Blocking Lys583 UFMylation destabilized the CMG complex, delaying origin firing and slowing replication fork progression.

Conclusions:

  • MCM5 UFMylation is essential for efficient origin firing and replication fork progression.
  • This process is critical for accurate DNA replication and cell proliferation.
  • MCM5 UFMylation plays a role in preventing MPD disorders.