Researchers unravel how the 'guardian of our genome' works

6 April 2021• PRESSRELEASE

LUMC scientists have discovered how certain proteins ensure that mistakes made in DNA during replication are repaired. They have used cryo-electron microscopy to make the MutS protein, also known as the guardian of our genome, visible. This enabled them to discover how this single protein is able to coordinate this essential DNA repair process from beginning to end. The results have been published in the scientific journal Nature Stucture and Molecular Biology.

"Cells divide continuously, that is the basis of all life on earth. In order to divide, the cells must first replicate their DNA," explains Meindert Lamers, associate professor at the Department of Cell and Chemical Biology. The protein DNA polymerase is responsible for this. "This protein builds a new DNA strand along the already existing one. Despite the fact that DNA polymerase works very precisely, some mistakes still slip through." 

Erasing mistakes

It is essential that these errors are repaired, since they may lead to the development of cancer. Fortunately, DNA polymerase has its own eraser, an exonuclease. In an earlier publication in Nature Communications, Lamers and colleagues describe how the DNA strand in which the error is made, can move from the DNA polymerase to the exonuclease without getting lost. Lamers: "There is a well-defined highway between these two proteins through which errors can be quickly repaired."

Unfortunately, this protein cannot erase all errors. "Nature has come up with a solution to this problem", says Lamers, "the protein MutS searches 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 detecting errors, but also in initiating and ending the repair of the mutation." Until now, it was unclear how one protein could coordinate so many different processes.

Molecular acrobatics

The researchers explain this in their most recent publication. "We were able to make the protein MutS visible with an advanced electron microscope whereby proteins are frozen. This allowed us to study the protein from different angles and to use computer models to create a 3D structure that helped us to determine its molecular composition. As a result, we discovered that the protein can take on many different forms. This molecular acrobatics enables the protein to attract multiple proteins and thus coordinate the entire DNA repair process." 

Left: a modern electron microscope. Centre: image from an electron microscope in which the individual MutS protein molecules are visible. Right: Two MutS proteins together form a pair that encloses the DNA (black) and looks for errors.

For this study, Lamers collaborated with Rafael Fernandez-Leiro of the Spanish cancer institute CNIO and professor Titia Sixma of the Netherlands Cancer Institute. The researchers emphasise that unravelling 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. Then, it took us 20 years to visualise the other three structures."

Essence of life

According to Lamers, it is very important to understand the repair process of our DNA in detail. "The process of making a copy of the DNA for the next generation of cells is the same for every living creature on earth." According to Lamers, this fundamental knowledge about how DNA polymerase, the exonuclease, and the MutS protein work, contributes to a better understanding of how innate changes in one of these proteins lead to frequent mutations and therefore an increased risk of cancer. This is the case, for example, in Lynch syndrome and endometrial cancer.

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