Replisomes contain up to 50 different proteins that participate in the delicate process of copying genetic material. Some proteins open DNA's double helix, others twist it to favor copying, others stabilise it, etc. They all move together through the genome to ensure a complete copy.

Scientists previously observed that the parts of the genome where the DNA was copied were also very rich in the modification by some very particular proteins, SUMOylations, and poor in others, ubiquitinations, but they were unable to understand why.

The continuation of the paper, published today in the Nature Structural & Molecular Biology journal, reveals how the balance between these chemical markers in these regions is, in fact, key for the division of genetic material. During this process, the USP7 protein travels with an entourage of molecules that form part of the replisome -- a set of proteins involved in copying the DNA -- and eliminates the ubiquitination marks of proteins in the complex, thus explaining the low concentration of ubiquitin in these areas.

In order to understand the role of USP7 and its cutting action on ubiquitin marks during the DNA copying process, the researchers used advanced protein tools.
"We knew that replisome proteins could present both modifications simultaneously [ubiquitinations and SUMOylations], but we did not know how they worked," explains the author. "We now know that USP7 eliminates the ubiquitin marks on proteins that are also SUMOylated in replication areas, which explains why there is a low concentration of ubiquitin and high levels of SUMO."

This balance between SUMO and ubiquitin establishes a code that regulates the concentration of proteins in the replisome. "If a protein is SUMOylated, it becomes enriched in the replisome, but if it is also ubiquitinated, it is expelled. This is a code of signals or flags that regulates the concentration of factors in the DNA replication area," say the researchers.

Apart from being of academic interest, these studies are relevant for chemotherapy. USP7 inhibitors are currently being studied as possible anti-cancer agents in pre-clinical tests.

https://www.cnio.es/ing/publicaciones/cnio-scientists-have-discovered-a-code-of-signals-that-regulates-genome-duplication