In 2013, Oscar Fernandez-Capetillo, currently at Karolninska Institutet/SciLifeLab, and co-workers performed the first proteomic analysis of the human replisome (Lopez-Contreras et al Cell Reports 2013). Besides providing a panoramic view of the proteins that are enriched around sites of DNA replication, this work noted an interesting phenomenon. Human proteins are “flagged” by being linked to other small proteins such as ubiquitin (Ub) or SUMO. These marks are known to regulate processes on the modified protein such as the stability of the protein or its localization. The authors noted that the overall levels of SUMO were high at sites of DNA replication, while the levels of Ub were low. What this meant, they did not know. 

In a current manuscript (Lecona et al Nature Struct Mol Biol 2016), the researchers explored how this balance between different modifications was kept around sites of DNA replication. They discovered that a de-ubiquitinase known as USP7 was enriched around replisomes, where it removed Ub moieties from other proteins. This explained why Ub levels are low at sites of DNA replication. Interestingly, the authors discovered that USP7 was able to eliminate Ub from SUMO. This “hybrid-chains” of different protein modifications, like Ub-SUMO, were known to exist but their function was mostly unknown. 

The new work reveals that SUMO and Ub create a flag-code which marks proteins to be recruited to, or evicted from, the replisome. The modification of a protein by SUMO, facilitates its concentration at replisomes. However, the combined modification SUMO-Ub is a mark that evicts proteins from DNA. In this manner, the role of USP7 is that of a traffic-policeman so to say. By controlling the levels of “stay” or “go” modifications on proteins, it helps to concentrate them at sites of DNA replication and thereby facilitate the duplication of the genome.

This work is also relevant from the drug-development point of view, the area where Fernandez-Capetillo is developing his research at SciLifeLab, since several USP7 inhibitors are being developed for anticancer treatment. The current manuscript challenges the previously proposed mechanism of action of these drugs, and raises some caution on the potential broad effects of these drugs not only on cancer cells but also on normal cells.