DNA ‘ambulance’ discovery may shed light on origins of cancer

Researchers have revealed how severely damaged DNA is transported within a cell to a site for repair – a discovery that could offer further explanation as to how cancer develops.

“Scientists knew that severely injured DNA was taken to specialized ‘hospitals’ in the cell to be repaired, but the big mystery was how it got there,” explains study author Karim Mikhail, a professor in the Department of Laboratory Medicine and Pathobiology at the University of Toronto.

“We’ve now discovered the DNA ‘ambulance’ and the road it takes.”

Cell DNA is often damaged as part of the cell’s regular processes, with by-products of these processes such as reactive oxygen often responsible for damage including the breaking of DNA strands or the formation of disruptive lesions.

When a chromosome suffers a double-strand break, it is unable to replicate itself properly. After being damaged in this manner, the DNA is taken to an area in the cell known as a nuclear pore complex for repair, stabilizing the DNA and allowing it to be replicated once more.

The researchers from the University of Toronto were aided by senior investigator Daniel Durocher, of Mount Sinai’s Lunenfeld-Tanenbaum Research Institute. With his assistance, the team used advanced microscopy to track the movement of damaged DNA in living yeast cells.

They discovered that the kinesin-14 motor protein complex helps mediate the interactions between double-strand breaks and nuclear pore complexes to ensure that cells survive via a DNA repair process.

However, the researchers also discovered during their study that this repair process is prone to error. Crucially, if DNA is repaired inaccurately, the instructions it contains for the genetic information within will be irregular.

“This process allows cells to survive an injury, but at a great cost,” Mekhail explains. “The cell has a compromised genome, but it’s stable and can be replicated, and that’s usually a recipe for disaster.”

There may be further ‘ambulances’ to discover

According to Durocher, when chromosomes are repaired incorrectly after a severe break, cancer frequently occurs. “This work teaches us that the location of the break within the cell’s nucleus has a big impact on the efficiency of repair,” he adds.

Following on from this discovery, the team is now attempting to find more so-called DNA  “ambulances,” which they say could lead toward the identification of targets for a new family of anticancer drugs.

“Scientists have been searching for this DNA ambulance for a long time and now we suspect there may be more than one,” says Mekhail. “It’s exciting because it’s a whole new area of research.”

Their findings could also lead to further discoveries relating to a wide range of different conditions.

The processes we’re studying are fundamental to the basic survival of a cell,” says first author Daniel Chung, a graduate student at Toronto. “Almost every aspect of disease can be linked to problems with DNA.”

Chung and his colleagues’ study, published in Nature Communications, is not the only one to be published recently revealing new information about DNA repair. Earlier this month, Medical News Today reported on a study of a mechanism used to repair single-strand breaks previously deemed inaccessible.

In the study, researchers describe how a particular enzyme can sense single-strand breaks by “riding” along a DNA coil, acting almost like a proof-reader by triggering reactions upon discovering a break that lead to repairs.

Written by James McIntosh



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