Guardian of our genome unraveled

Cells are continuously dividing, which is the essence of all life on Earth

LUMC scientists have discovered how certain proteins ensure that errors that occur in the DNA during the copying process are repaired. They have been able to visualize the MutS protein that plays a major role in this, also known as the guardian of our genome, using cryo-electron microscopy. For example, they have discovered how this single protein is able to coordinate this essential DNA repair process from start to finish. The results are published in the journal Nature Stucture and Molecular Biology.

“Cells are continuously dividing, that is the essence of all life on earth. To be able to divide, the cells must first copy their DNA, ”explains Meindert Lamers, associate professor in the Department of Cell and Chemical Biology. The protein DNA polymerase is responsible for this. “This protein builds a new DNA strand along the existing strand. Despite the fact that DNA polymerase works very accurately, mistakes sometimes slip through. ”

Erasing mistakes
It is essential that these errors are corrected or else they can lead to the development of cancer. Fortunately, DNA polymerase has its own eraser, an exonuclease. In a previous publication in Nature Communications, Lamers and colleagues describe how the DNA strand that is faulty can move from the DNA polymerase to the exonuclease without getting lost. Lamers: “There is a kind of highway between these two proteins, which makes it easy to correct errors.”

Unfortunately, this protein cannot erase all mistakes. “Nature has also come up with something for this,” says Lamers, “the protein MutS is looking for a needle in a haystack. It scans the copied DNA for errors that occur once in a million DNA letters. MutS is not only involved in debugging, but also in the initiation and completion of the mutation repair. ” Until now, it was unclear how one protein could coordinate so many different processes.

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Molecular acrobatics
The researchers answer this in their most recent publication. “We were able to visualize the MutS protein with an advanced electron microscope in which proteins are frozen. This allowed us to study the protein from multiple angles and ultimately use computer models to arrive at a 3D structure that allowed us to determine the molecular composition. As a result, we discovered that the protein can take many different forms. These molecular acrobatics enable the protein to attract multiple proteins and thus coordinate the entire DNA repair process. ”

For this research, Lamers collaborated with Rafael Fernandez-Leiro from the Spanish cancer institute CNIO and professor Titia Sixma from the Netherlands Cancer Institute. The researchers emphasize that the unraveling of these protein structures is only possible due to the enormous technological developments in electron microscopy in recent years. Lamers: “During my PhD, we identified the first structure that MutS could adopt. It then took us 20 years to visualize the other three structures. ”

Essence of life
According to Lamers, it is very important to understand in detail the repair process of our DNA. “Making a copy of the DNA for the next generation of cells is the same for every living thing on Earth.” This fundamental knowledge about the method of DNA polymerase, the exonuclease, and the MutS protein, according to Lamers, contributes to more insight into how innate changes in one of these proteins lead to mutations and thus increase the risk of cancer many times over. This is the case, for example, with Lynch syndrome and endometrial cancer.

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