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Results for “UFL1”

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3 recordsLinked to original sources

PubMed2025

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.

DNA Replication↗

PubMed2026

A Phosphoproteomic Platform Identifies Erythrocyte Membrane Protein Band 4.1-Like 3-Mediated Lipid Droplet Remodeling Linked to Liver Cancer Invasion and Migration.

Aberrant lipid metabolism is a hallmark of hepatocellular carcinoma (HCC), yet the regulatory mechanisms governing lipid droplet (LD) dynamics and their contribution to tumor progression remain poorly understood. Here, we developed an ultrasensitive phosphoproteomic platform using high-affinity HPDA@Ti4+ nanospheres to map LD-associated phosphorylation events across six HCC cell lines. By correlating phosphoproteomic signatures with LD morphology, we identified distinct regulatory signatures associated with LD size and abundance. Functional perturbation screens identified two distinct phosphoprotein modules controlling LD size: silencing SH3KBP1, SLK, EHD2, EPB41L3, and NEXN reduced LD size in Huh1 cells, whereas silencing CPD, BET1, UFL1, RRP1B, OGFR, and CD2BP2 enlarged LDs in Huh7 cells. Notably, we identified EPB41L3 as a critical metabolic-metastatic link; its loss decreased LD size and accelerated HCC migration and invasion, correlating with poor clinical prognosis. Crucially, we identified five key phosphorylation sites on EPB41L3 essential for its function; substituting these with alanine completely abolished its regulatory control over both LD size and HCC metastatic potential. Together, these findings delineate a phosphorylation-based regulatory network controlling the LD architecture and metastatic potential in HCC. Our study not only identifies potential therapeutic targets but also establishes a generalizable phosphoproteomic framework for interrogating lipid signaling in cancer metabolism.

Humans↗

PubMed2024

PARP1 UFMylation ensures the stability of stalled replication forks.

The S-phase checkpoint involving CHK1 is essential for fork stability in response to fork stalling. PARP1 acts as a sensor of replication stress and is required for CHK1 activation. However, it is unclear how the activity of PARP1 is regulated. Here, we found that UFMylation is required for the efficient activation of CHK1 by UFMylating PARP1 at K548 during replication stress. Inactivation of UFL1, the E3 enzyme essential for UFMylation, delayed CHK1 activation and inhibits nascent DNA degradation during replication blockage as seen in PARP1-deficient cells. An in vitro study indicated that PARP1 is UFMylated at K548, which enhances its catalytic activity. Correspondingly, a PARP1 UFMylation-deficient mutant (K548R) and pathogenic mutant (F553L) compromised CHK1 activation, the restart of stalled replication forks following replication blockage, and chromosome stability. Defective PARP1 UFMylation also resulted in excessive nascent DNA degradation at stalled replication forks. Finally, we observed that PARP1 UFMylation-deficient knock-in mice exhibited increased sensitivity to replication stress caused by anticancer treatments. Thus, we demonstrate that PARP1 UFMylation promotes CHK1 activation and replication fork stability during replication stress, thus safeguarding genome integrity.

DNA Replication↗