Our DNA is quite prone to damage. The genetic milieu that resides within the nucleus of each cell is often under assault from external environmental factors like UV light or internal features such as free radicals that form during normal cellular metabolic processes. Furthermore, the act of DNA replication can introduce errors leading to DNA strand breakage. Luckily evolution has seen fit to select for proteins that will recognize and repair the aftermath of the daily onslaught that nuclear DNA undergoes.
DNA double-strand breaks (DSBs) are of particular concern to the molecular repair machinery, as this type of DNA damage is often associated with chromosomal breakage, deficient repair, and the development of cancer. Typically, severely damaged DNA is transported to special areas within the nucleus for repair. However, the specific mechanism underlying that process has eluded scientists for many years.
Now, researchers from the University of Toronto have discovered how certain DNA DSBs are transported within the cell and how they are repaired once there—a discovery that could provide vital insight into the development of certain forms of cancer.
“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,” explained senior author Karim Mekhail, Ph.D., associate 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.”
The findings from this study were published recently in Nature Communications through an article entitled “Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process.”
The researchers found that that the kinesin motor protein complex called Cik1–Kar3 partnered with chromatin remodeling molecules to shuttle DSB regions to the nuclear pore complex and initiate the DNA repair process known as break-induced replication—a particularly inefficient repair mechanism.
“This process allows cells to survive an injury, but at a great cost,” said Dr. Mekhail. “The cell has a compromised genome, but it's stable and can be replicated, and that's usually a recipe for disaster.”
In addition to the molecular techniques, the researchers used to understand the repair mechanisms, they also employed some advanced microscopy techniques to track the DNA ambulance complex’s translocation within the nucleus.
“Cancer often occurs when our chromosomes break and are misrepaired,” noted co-author Daniel Durocher, Ph.D., a senior investigator at Mount Sinai's Lunenfeld-Tanenbaum Research Institute. “This work teaches us that the location of the break within the cell's nucleus has a big impact on the efficiency of repair.”
The Toronto scientists were excited about their findings and believe the implications from their research could extend to an array of developmental and disease states.
“We expect that this may allow us to identify targets for a new class of anti-cancer drugs,” stated Dr. Mekhail. “Scientists have been searching for this DNA ambulance for a long time and now we suspect there may be more than one. It's exciting because it's a whole new area of research.”