MCM5 UFMylation regulates replication origin firing and fork progression

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.

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Publication Details

Journal
The EMBO Journal
Published
2025-09-12
DOI
https://doi.org/10.1038/s44318-025-00562-6
Citations
1
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.81

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article

MCM5 UFMylation regulates replication origin firing and fork progression

Yisui Xia, Shunichi Takeda, Bin Peng, Xingxuan Wu et al.
1 citations
The EMBO Journal
DNA Repair Mechanisms
0.81
article

MCM5 UFMylation regulates replication origin firing and fork progression

Yisui Xia, Shunichi Takeda, Bin Peng, Xingxuan Wu, Xingzhi Xu, Yuanliang Zhai, Yanting Liao, Liu Liu, Zheng Li, Mengting Liu, S.F. Rao, Qiongdan Zhang
article en
1 citations

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.

The EMBO JournalVol. 44(21)
Shenzhen University (CN), Hong Kong University of Science and Technology (HK), Shenzhen Occupational Disease Prevention Hospital (CN), Shenzhen University Health Science Center (CN), Guhua Hospital (CN), University of Hong Kong (HK), Capital Normal University (CN)
National Natural Science Foundation of China, Science, Technology and Innovation Commission of Shenzhen Municipality, Guangdong Provincial Pearl River Talents Program
Openalex Percentile: Top 24%
DNA Repair Mechanisms
0.81
DOIOpen Access PDFOpenAlex
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