Study Identifies Key Protein Involved in DNA Replication Process

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A recent study has identified a protein that plays a crucial role in determining how cells manage DNA replication. Published in Nature Communications, the international team of researchers uncovered that the protein USP50 regulates the use of specific enzymes—nucleases and helicases—during DNA replication. These enzymes are vital for both promoting ongoing replication and resolving issues when the replication process is stalled.

Led by Jo Morris from the University of Birmingham’s Department of Cancer and Genomic Sciences, the team discovered that USP50 is responsible for guiding which helicases and nucleases are employed during DNA replication, fork restart, and the maintenance of telomeres—the DNA-protein complexes at the ends of chromosomes. According to the researchers, this discovery offers a deeper understanding of the mechanisms behind DNA replication and its errors, which may contribute to certain hereditary conditions.

Coordinating DNA Replication Enzymes
“Our study concerns how our cells use specific enzymes to support the typical regulation of DNA replication,” explained Morris, the lead author of the study. “We found that because there are several different enzymes involved in cleaving and unwinding, cells must regulate which ones they use so that replication can happen properly. We identified that protein USP50 is involved in this regulation. This discovery may be an important step to understanding how some hereditary gene changes lead to early onset aging and cancer.”

The enzymes helicases and nucleases play distinct roles in managing the replication fork—helicases unwind the DNA helix, while nucleases cut the DNA where necessary. Proper coordination of these enzymes is essential to avoid replication errors. The identification of USP50’s role highlights a complex regulatory system that determines when each enzyme is needed, ensuring that replication proceeds without interruption.

Defects in the Absence of USP50
The research also revealed that when USP50 is absent, the cells attempt to continue replication by employing various helicases and nucleases in an uncoordinated manner. This disordered approach leads to replication defects, which could have serious implications for genome stability.

“The finding that cellular nucleases and helicases can stop replication in certain sections of DNA was a surprise,” said Morris. “It shows that cells closely coordinate their toolkit of DNA-processing enzymes to ensure successful DNA replication.”

Disruptions in this process can lead to genomic instability, which is linked to conditions such as cancer and premature aging. Understanding how proteins like USP50 regulate these enzymes opens new avenues for exploring the causes of these conditions.

Implications for Genome Stability and Future Therapies
Co-author Simon Reed, from Cardiff University’s Division of Cancer and Genetics, emphasized the broader significance of this research. “This research sheds light on the complex mechanisms that protect our cells from DNA damage,” said Reed. He noted that the findings could influence future therapeutic strategies aimed at maintaining genome stability and preventing diseases caused by DNA replication errors.

Publication Details
Mackay, H.L., Stone, H.R., Ronson, G.E. et al. USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication. Nat Commun 15, 8102 (2024). https://doi.org/10.1038/s41467-024-52250-4