An international study revealed the function of the “guardian” of the genome, that is, the protein that repairs DNA errors.
Scientist from Genome Integrity and Structural Biology Group Who drives Rafael Fernandez Leiro Researchers from the National Cancer Research Center (CNIO) have discovered how certain proteins are guaranteed to repair errors caused during DNA replication.
They used electron cryomicroscopy to prepare MutS protein, also known as MutS protein. guardian Of the genome, allowing them to describe how this single protein coordinates this essential DNA repair process from start to finish.
The research was conducted in collaboration with Meindert Lamers of Leiden University Medical Center in LUMC, the Netherlands, and Titia Sixma from the Netherlands Cancer Institute and Oncode Research Institute.Their results are published in Natural structure and molecular biology.
When the mechanism fails
Between the different stages of cell division is DNA replication, during which DNA polymerase replicates the genetic information of the cell to transfer it to daughter cells. Although the mechanism is very precise, errors occasionally occur. These errors must be repaired, otherwise it will lead to tumor development.
Researchers have described in previous work that DNA polymerase has its own corrector, an exonuclease, which allows it to correct errors introduced during DNA replication.
However, when the corrector is insufficient, the MutS protein will enter the scene, scan the copied DNA for errors, and then initiate and complete the repair of those proteins it detects. But until now, it is not clear how a single protein orchestrates so many different processes. Now published international studies have successfully revealed this mechanism.
“Using electron cryomicroscopy, we can observe it while it performs its function, and capture its molecular structure in a continuous conformation. With this information, we can understand how individual proteins coordinate the entire process, which must be very Precise”, Rafael Fernández-Leiro explained.
The mechanism of cancer
An in-depth understanding of our DNA repair process, which involves DNA polymerase itself, exonuclease and MutS protein, is essential to understand how changes in any of these proteins lead to mutations and therefore increase mutations. The risk of developing certain types of tumors, such as Lynch syndrome or endometrial cancer.
The researchers emphasized that due to the tremendous advances in electron microscopy technology in recent years, it is possible to understand the structure of proteins.
Metastasis depends on the survival of cancer cells
“Electron cryomicroscopy allows us to obtain very high-resolution images while the protein is functioning. Using these images, we can reconstruct the three-dimensional structure of the protein on a computer and generate an atomic model that allows us to understand its work. Principle”, Fernández-Leiro continued.
Image obtained through a microscope
The background of the image is a photo taken with an electron microscope, in which DNA molecules modified with MutS protein molecules are observed.
Scan for errors in the DNA (after image processing, the center circle highlights one of them). The lower part shows the MutS structure in different stages of the repair process solved in this work. / CNIO
The research was funded by the Ministry of Science and Innovation, Carlos III Health Institute, National Innovation Agency, British Medical Research Council, Oncode Institute, NWO-Gravity and Horizontes 2020.
The selection process to authorize DNA mismatches for repair.Rafael Fernandez Leiro Wait (Natural structure and molecular biology, 2021). DOI: 10.1038 / s41594-021-00577-7