Xeroderma pigmentosum (XP) is a rare condition. Due to an error in the DNA repair process, sunlight causes a lot of damage in the genome of these patients. “This makes them extremely sensitive to sunlight and develops skin cancer,” says dermatologist Remco van Doorn. “But not the two patients I recently saw in my consulting room.” These brother and sister with XP were more sensitive to sunlight, but mainly suffered from neurological problems, such as a coordination disorder.
unravel DNA
But no skin cancer yet, and that is strange with this condition, thought Van Doorn. To find out exactly how this works, he approached molecular biologist Martijn Luijsterburg, group leader at the Department of Human Genetics. “We examined the DNA of these patients to find an answer to this question,” says Luijsterburg.
They specifically looked at how damage to the DNA of these patients is repaired. “Normally this takes place in two ways. The first, global genome repair, clears up the bulk of DNA damage. The second, transcription-linked repair, clears the damage that gets in the way of reading the DNA,” explains Luijsterburg. Both ways use the repair protein XPA. “We found that the patients had exactly the same error in the XPA protein.”
One mistake, two effects
But what exactly is the effect of this error? To find out, Diana van den Heuvel, a researcher in Luijsterburg’s team, made cells in the lab with the same error in the XPA protein and compared them with cells from the patients. “That’s how we found out that the global repair route was still pretty much intact. The DNA is therefore still reasonably well repaired in this way. This explains the slight sensitivity to the sun and the absence of skin cancer so far,” Van den Heuvel thinks. The other repair process virtually ceased to take place. “We think that the damage left in the DNA due to the lack of this repair pathway is responsible for the neurological problems.” A good example of how one DNA error can have multiple and diverse consequences.
From clinic to the lab: a successful collaboration
“It is remarkable that a question that arises from a clinical observation leads to new insights into such a fundamental process as DNA repair,” says Van Doorn. “This research shows once again how complex the repair of UV damage in DNA is. If we better understand this process, we will hopefully also gain more insight into why some people develop skin cancer and others do not.”