Related Experiment Video
Updated: Jan 18, 2026
Author Spotlight: Investigating the Motion Dynamics of the Eukaryotic Replisome Components at the Single-Molecule Level
Published on: July 26, 2024
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.
Abstract:
Modification with UFM1 (UFMylation) is essential for cell proliferation, but its precise mechanism of action is unclear. Furthermore, the UFMylation pathway has been associated with microcephalic primordial dwarfism (MPD) disorders, and mutations causative for MPD are also identified in genes encoding components of the replicative DNA helicase complex, including the MCM hexamer. Here, we reveal that UFMylation regulates DNA replication, and that all MPD-associated mutations in UFMylation enzymes impair replication. Mechanistically, the UFM1 E3 ligase UFL1 catalyzes Lys583 UFMylation of MCM5, a critical component of the CMG replicative DNA helicase complex. Mutation of Lys583 blocking this UFMylation event destabilizes the helicase complex, delaying origin firing and slowing replication fork progression. We conclude that MCM5 UFMylation is essential for efficient origin firing and replication fork progression, both of which ensure accurate DNA replication, cell proliferation, and prevention of MPD disorders.
Insights
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.
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.
More Related Videos
08:53Strand-Specific Analysis of Proteins at Replicating DNA Strands by Enrichment and Sequencing of Protein-Associated Nascent DNA Method
Published on: May 2, 2025
11:19Inducing a Site Specific Replication Blockage in E. coli Using a Fluorescent Repressor Operator System
Published on: August 21, 2016
Related Concept Videos
02:37Restarting Stalled Replication Forks
02:37Restarting Stalled Replication Forks
01:29Replication in Eukaryotes
Many Proteins Orchestrate Replication at the Origin
Eukaryotic replication follows many of the same...
02:31Replication in Eukaryotes
01:02The DNA Replication Fork
01:02The DNA Replication Fork