MCM5 UFMylation regulates replication origin firing and fork progression
- EMBO J. 2025 Nov;44(21):6019-6050. doi: 10.1038/s44318-025-00562-6.
- 1. Guangdong 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.
- 2. Shenzhen University General Hospital-Dehua Hospital Joint Research Center on Precision Medicine (sgh-dhhCPM), Dehua Hospital, Dehua, China.
- 3. Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China.
- 4. College of Life Sciences, Capital Normal University, Beijing, China.
- 5. School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
- 6. South China Hospital, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University Medical School, Shenzhen, China.
- 7. Division of Life Science, The Hong Kong University of Science & Technology, Hong Kong, China.
- 8. Guangdong 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. [email protected].
- 9. Guangdong 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. [email protected].
- # Contributed equally.
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.