The newly identified DNA repair protein has the name STK19 and wasn’t entirely unknown to scientists, explains professor Jurgen Marteijn from Erasmus MC: “Previous studies suggested that this protein might be linked to DNA repair. There wasn’t any conclusive evidence yet, but we thought: if there’s so much smoke, there must be fire.” And that proved to be the case, as the researchers describe in the scientific journal Molecular Cell.
DNA damage is a part of life. From sunlight and smoking, to even our own metabolism - our genetic material is constantly taking damage. This adds up to tens of thousands of damages per day in every cell. DNA damage is a problem for the cell because it can interfere with the process of reading genes. If this transcription process fails, the cell cannot produce the proteins needed for proper functioning, potentially leading to aging-related diseases. That’s why cells are constantly working towards detecting and repairing DNA damage, for which it uses various repair proteins that work together in a complex molecular machine.
The researchers found that STK19 acts like molecular glue. As a "big connector", it holds together various proteins that form the DNA repair complex. It also plays another crucial role in this repair pathway: it recruits other proteins that ultimately cut out the damaged part of the DNA. These two processes ensure that gene transcription can continue smoothly, even in the case of DNA damage.
“A very essential player indeed”, concludes Anisha Ramadhin, a PhD student at Erasmus MC. She conducted several experiments with cells that lack STK19, and observed that transcription-disrupting DNA damage was not properly repaired in these cells. “This shows us how crucial this protein is in DNA repair.” Ramadhin is proud of the discovery: “This is what I find fulfilling: solving the unknown, creating hypotheses, devising sub-questions, and doing increasingly complex experiments at each step. This was a fun puzzle to solve.”
It is very important to gain more knowledge about the way the DNA repair reaction works, Marteijn emphasizes: “A well-functioning repair machine protects us against aging. Conversely, problems with DNA repair lead to aging-related diseases. We see this play out to a more extreme degree in patients with the rare Cockayne syndrome, but DNA damage also accumulates in healthy individuals over a lifetime.”
For this research, Marteijn joined forces with fellow Oncode Investigator Titia Sixma, uniting their individual disciplines of genome stability and structural biology to unravel the mysteries of the DNA damage response. Sixma is an expert in the field of protein analysis. Post-doctoral fellow Shun-Hsiao Lee performed the protein purifications and noticed that even in an ‘in vitro’ situation where all proteins are taken outside of the cell, the STK19 protein functions as glue. Shun: "It is exciting to see that STK19 can interact with the DNA repair complex in our reconstituted biochemistry setup, and plays important roles in its regulation. This allows us to study the mechanisms further in detail."
