Cryo-EM reveals how ‘911’ molecule helps repair damaged DNA

The image shows how the 911 clamp is loaded onto the DNA. Credit: Dr Huilin Li, Van Andel Institute

When something goes wrong during DNA replication, cells call their own version of 911 to interrupt the process and fix the problem, a fail-safe essential to maintaining health and preventing disease.

Today, scientists from the Van Andel Institute and Rockefeller University have for the first time revealed how a key part of this repair process – aptly called the 911 DNA checkpoint clamp – is recruited to the site of DNA damage. The findings, published today in Structural and Molecular Biology of Nature, illuminate new insights into how cells ensure that genetic instructions are correctly passed from one generation of cells to the next. The project was led by study co-corresponding authors Huilin Li, Ph.D., of VAI, and Michael E. O’Donnell, Ph.D., of Rockefeller University and the Medical Institute Howard Hughes.

“DNA damage can have serious consequences, including cancer and other diseases. Because of this, our cells have a host of checks and balances to ensure DNA integrity,” said Li. “Our high-resolution structure of the 911 DNA checkpoint clamp as it interacts with the molecule that loads it onto the DNA strand gives us detailed insight into the essential DNA repair process. We hope that this knowledge can be used for the development of new therapeutic strategies for diseases related to DNA damage.

Every day, billions of cells in the human body are replaced by cell division, a process in which one cell splits into two. This fundamental function stimulates growth and facilitates the maintenance of tissues such as skin and muscle. A central part of this system is DNA replication, in which our genetic instruction manual is carefully reproduced to ensure that every cell has an exact copy.

DNA damage can result from errors in this process or from other factors that directly harm DNA, such as exposure to UV rays from the sun or carcinogens such as tobacco smoke. In the event of damage, cells have emergency response systems to halt replication until the problem can be repaired or to kill the cell, preventing the transmission of incorrect information.

This is where the 911 DNA Checkpoint Clamp comes in. When DNA damage is detected, the ring-shaped clamp is loaded onto the DNA and transported to the site of the error. Once there, it sends a signal to stop cell division while signaling other repair molecules to remove damaged DNA and replace it with a corrected sequence.

The structure was determined through the use of VAI’s cryo-electron microscopes (cryo-EM), which allow scientists to visualize molecular structures at the atomic level. In the case of the 911 DNA checkpoint clamp, cryo-EM also revealed a surprise: rather than loading onto DNA from the 3′ (or “first three”) end like all other known DNA clamps, the 911 clamp is loaded onto DNA from the opposite end, called the 5′ (“first five”) end. This new and unexpected discovery reshapes what we know about DNA replication and paves the way for further studies in this area.


Scientists examine the impact of a very specific defect in DNA replication


More information:

Michael O’Donnell, DNA is loaded through the 9-1-1 DNA checkpoint clamp in the opposite direction to the PCNA clamp, Nature Structural and Molecular Biology (2022). DOI: 10.1038/s41594-022-00742-6. www.nature.com/articles/s41594-022-00742-6

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Van Andel Research Institute


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