Keeping DNA damage-free is one of the cell’s most important tasks. After all, DNA contains crucial information to ensure proper cell function. Scientists led by Prof. Dr. Ir. Jurgen Marteijn have discovered a new way to repair DNA damage.
It concerns a form of damage that hasn’t been extensively researched. In this specific type of DNA damage, a protein becomes stuck on the DNA. This type of damage is called DNA-protein crosslinks. ‘Proteins often bind to DNA, but a protein shouldn’t be permanently stuck there: you should see it as a big pimple on the DNA that cannot be removed,’ explains Marteijn. Such a protein pimple forms a physical blockade for various processes in the cell that occur on the DNA. It is already known that DNA-protein crosslinks pose a problem when the cell wants to divide and needs to duplicate the DNA for it. This process is disrupted, which can lead to mutations and cancer.
How does a pimple form on DNA?
In DNA-protein crosslinks, a protein that shouldn’t be there becomes stuck to the DNA. This can happen in two ways. Proteins can be ‘glued’ to DNA by molecules from outside the body, including certain chemotherapeutics used in cancer treatment. Or proteins are immobilized by endogenous substances released during normal metabolism or alcohol breakdown.
Now it appears that protein pimples also cause problems during the process of reading the genes in the DNA to make new proteins. The protein pimple blocks this crucial process called transcription, preventing the cell from functioning properly. In Nature Cell Biology, the Rotterdam scientists describe how the stuck protein is removed from the DNA, allowing the genes to be read again.
Two proteins named CSA and CSB play an important role in this process. Through a hitherto unknown mechanism, they initiate a reaction that leads to the breakdown of the stuck protein.
CSA and CSB are well-known in the DNA repair field because a mutation in these proteins leads to the rare and severe Cockayne syndrome. Key features of this disease include accelerated aging and loss of nerve cells, or neurodegeneration. ‘This likely happens because DNA damage caused by DNA-protein crosslinks cannot be repaired by CSA and CSB. The damage accumulates rapidly, and cells can no longer function properly or die’, explains postdoctoral researcher Dr. Marjolein van Sluis.
Age-related brain diseases
But their findings are also important for people who don’t suffer from Cockayne syndrome, the researchers argue. Marteijn: ‘What happens accelerated in these patients probably also happens to us, but at a later age. The older you get, the more the damage caused by DNA-protein crosslinks accumulates. Healthy cells repair damage very efficiently, but occasionally it doesn’t go quite right, causing more and more protein pimples to accumulate in our DNA as we age. This is especially problematic for cells that last a lifetime, such as brain cells. Due to the accumulating unrepaired damage, they gradually work less well.’ This can ultimately lead to age-related brain diseases, such as dementia.
Marteijn and colleagues therefore expect that further research will focus on the link between neurodegenerative aging diseases and damage caused by DNA-protein crosslinks. ‘Given the aging population, this is an important.
