This is how the ‘guardian’ of the genome works

A team from the National Cancer Research Center (CNIO) has discovered how certain proteins guarantee the repair of errors caused in DNA during its replication. Using electron cryomicroscopy, the group led by Rafael Fernandez-Leiro has made visible the MutS protein, also known as the ‘gatekeeper’ of our genome, which allowed them to describe how this single protein is able to coordinate this essential DNA repair process from start to finish.

The study has been carried out in collaboration with Meindert Lamers, Leiden University Medical Center, LUMC (Netherlands), and Titia Sixma, from the Netherlands Cancer Institute and the Oncode Institute. Their results are published in Nature Structural & Molecular Biology.

Between the different phases of the cellular division DNA replication is encountered, during which DNA polymerase duplicates the cell’s genetic information in order to transfer it to the daughter cell. Despite being a very precise mechanism, errors can occasionally occur. It is essential that these errors are repaired, as otherwise they can cause tumors.

The authors have made visible the MutS protein, also known as the ‘guardian’ of our genome, and have described how this unique protein is able to coordinate the essential process of DNA repair from start to finish

Researchers had already described in previous work that DNA polymerase has its own corrector, an exonuclease, thanks to which it can correct errors that are introduced during DNA copying. But when this corrector is insufficient, the MutS protein enters the scene, which scans the copied DNA for errors and then initiates and completes the repair of those it detects.

Until now it was unclear how a single protein can coordinate so many different processes. “We have been able to observe it while it carries out its functions, capturing its molecular structure in successive conformations. With this information we have been able to understand how a single protein is capable of coordinating the entire process, which has to be extremely precise ”, explains Fernández-Leiro.

How mutations develop

Knowing in depth the repair process of our DNA, in which DNA polymerase itself, the exonuclease and the MutS protein are involved, is essential to understand how the alterations that occur in any of these proteins lead to mutations and, therefore so much, to a increased risk of developing certain types of tumors, such as Lynch syndrome or endometrial cancer.

The researchers insist on the important role of electron microscopy in unraveling the structures of proteins. “Electron cryomicroscopy makes it possible to obtain very high resolution images of proteins while they carry out their function. Using these images, we can reconstruct the three-dimensional structure of the protein in the computer and generate an atomic model to understand how it works ”, concludes Fernández-Leiro.

Reference:

Rafael Fernández-Leiro et al. ‘The selection process of licensing a DNA mismatch for repair’. Nature Structural & Molecular Biology, 2021. DOI: 10.1038 / s41594-021-00577-7

The study is funded by the Ministry of Science and Innovation, the Carlos III Health Institute, the State Innovation Agency, UK Medical Research Council, Oncode Institute, NWO-Gravity and Horizontes 2020.

Rights: Creative Commons.