Summary: Scientists have identified a protein, USP50, that helps direct which enzymes act on DNA during replication—deciding whether nucleases cut DNA strands or helicases unwind them. This regulation is essential for smooth, accurate DNA copying, especially when the replication machinery stalls and must restart. Cells lacking USP50 fail to coordinate these enzymes properly, producing replication errors that can undermine genome stability and contribute to disease.
The discovery clarifies an important layer of genome maintenance and offers a potential explanation for how some inherited genetic changes contribute to early-onset ageing and certain cancers. A clearer understanding of USP50’s role could guide future approaches to protecting DNA integrity under stress.
Key facts
- USP50 directs the selection of nucleases and helicases during DNA replication to preserve stability.
- Loss of USP50 causes misdirected enzyme activity and replication defects.
- Insights into USP50 improve our understanding of genome maintenance and may inform therapeutic strategies for related hereditary conditions.
Source: University of Birmingham
USP50 identified as a regulator of enzyme choice during DNA replication
A new paper in Nature Communications reports that USP50, a ubiquitin-specific protease, plays a key role in managing the balance between helicase and nuclease activities during mammalian DNA replication. The international research team, led by Professor Jo Morris from the University of Birmingham’s Department of Cancer and Genomic Sciences, found that USP50 helps determine which of several available DNA-processing enzymes are used during ongoing replication, fork restart, and telomere maintenance.
DNA replication requires a coordinated toolkit of helicases, which separate DNA strands, and nucleases, which can trim or cut DNA as needed. Proper coordination ensures replication proceeds without introducing breaks or errors. The study shows that USP50 is associated with chromatin and supports replication continuity, efficient restart of stalled forks, and the maintenance of telomeres—the protective DNA–protein structures at chromosome ends.
By identifying USP50’s regulatory role, the researchers provide a mechanistic explanation for how cells select appropriate enzyme activities at difficult-to-copy regions of the genome. Disruption of this selection process can leave DNA vulnerable to damage and instability, which over time may contribute to disease.
Professor Jo Morris, corresponding author and Professor of Molecular Genetics, commented: “Cells contain multiple helicases and nucleases, and they must deploy the correct ones at the right time. Our work shows USP50 plays a central part in that decision-making, helping replication proceed accurately and protecting genome integrity.”
Attempted workaround
The study also reveals what happens when USP50 is missing: cells attempt to recruit a broader, less coordinated set of nucleases and helicases to stalled forks. This unregulated activity can impede proper replication and create defects that threaten genomic stability. The team observed increased association of the DNA2 nuclease and the RECQL4 and RECQL5 helicases with nascent DNA in USP50-deficient cells, suggesting that these factors drive the observed replication problems in the absence of USP50.
“It was surprising to see that certain nucleases and helicases can actually stop replication of vulnerable DNA segments,” Professor Morris said. “This highlights how tightly cells must coordinate their DNA-processing enzymes to complete replication correctly.”
Professor Simon Reed, co-author and Co-Director of the Division of Cancer and Genetics at Cardiff University, added: “This research clarifies an important protective mechanism that helps prevent DNA damage. Understanding how USP50 suppresses harmful enzyme activities gives us better insight into genome stability and may inform future therapeutic strategies.”
About this genetics research news
Author: Tim Mayo
Source: University of Birmingham
Contact: Tim Mayo – University of Birmingham
Image: The image is credited to Neuroscience News
Original research: Open access. “USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication” by Simon Reed et al. Nature Communications
Abstract
USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication
Mammalian DNA replication depends on a range of helicase and nuclease activities to ensure accurate copying of the genome, but how cells direct those activities at particular sites has been unclear. This study identifies USP50 as a chromatin-associated protein that promotes ongoing replication, supports fork restart, helps maintain telomeres, and increases cellular survival under replication stress caused by agents such as hydroxyurea or G-quadruplex stabilizers.
The authors show that USP50 helps localize protective factors like WRN and FEN1 to stalled forks. In cells lacking USP50, nascent DNA becomes more associated with DNA2 nuclease and RECQL4/RECQL5 helicases, and the resulting replication defects are driven by these enzymes. Reducing DNA2 or RECQL4/RECQL5 activity improves survival and restores telomere stability in USP50-deficient cells, indicating USP50’s role in balancing helicase and nuclease use at active and stalled replication forks.