Related Experiment Video
Updated: May 21, 2025
10:11
Author Spotlight: Investigating the Motion Dynamics of the Eukaryotic Replisome Components at the Single-Molecule Level
Published on: July 26, 2024
913
USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination
Derek L Bolhuis1,2, Dalia Fleifel1, Thomas Bonacci2
1Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Nature Communications
|May 16, 2025
Summary
Human USP37 prevents premature replisome disassembly by deubiquitinating MCM7, maintaining active DNA replication. This deubiquitinase safeguards genome stability and protects cells from replication stress.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Eukaryotic DNA replication relies on the CMG helicase (CDC45-MCM2-7-GINS) within replisomes.
- Replisome assembly and disassembly are critical for genome stability and cell cycle progression.
- Factors preventing premature CMG helicase unloading and replisome disassembly are not well understood.
Purpose of the Study:
- To identify key deubiquitinases (DUBs) that prevent untimely CMG helicase unloading.
- To investigate the role of USP37 in maintaining replisome stability during S-phase.
- To explore the therapeutic potential of targeting USP37 in cancer.
Main Methods:
- Targeted loss-of-function genetic screen in human cells.
- Quantitative single-cell analysis of replisome dynamics.
- Proteomics and biochemical assays to identify protein interactions and enzymatic activity.
- Assessment of USP37's role in response to replication stress.
Main Results:
- USP37 was identified as a crucial DUB that prevents premature replisome disassembly.
- USP37 maintains active CMG helicase complexes on S-phase chromatin, promoting cell cycle progression.
- USP37 directly interacts with the CMG complex and deubiquitinates MCM7, antagonizing disassembly.
- USP37 confers protection to normal epithelial cells against oncoprotein-induced replication stress.
Conclusions:
- USP37 is essential for maintaining replisome integrity during S-phase.
- USP37 antagonizes ubiquitination-mediated CMG helicase disassembly.
- Targeting USP37 may offer a novel therapeutic strategy for cancers with impaired DNA replication control.
Related Concept Videos
00:50Anaphase Promoting Complex
2.8K
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
2.8K
02:37Restarting Stalled Replication Forks
5.7K
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
5.7K
01:32Export of Misfolded Proteins out of the ER
3.4K
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
3.4K
01:37The Unfolded Protein Response
4.3K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.3K
02:58Regulated Protein Degradation
7.1K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.1K
02:17Separation of Sister Chromatids
3.5K
At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
At the onset of anaphase, separase, a proteolytic enzyme, is...
At the onset of anaphase, separase, a proteolytic enzyme, is...
3.5K