Spatial Genome Organization and Rocket Science?!

Understanding precisely how damaged DNA gets repaired is an important avenue in developing better treatments for various diseases such as cancer.

Molecular biologists at work in this field sought fresh insight recently from a non-traditional source: University of Toronto’s Institute for Aerospace Studies. The results – published in Nature Communications this week – shed light on the movement of damaged DNA within the nucleus of the cell, a key step in the repair process.

The unusual biology-aerospace collaboration arose when U of T Medicine Prof. Karim Mekhail, Canada Research Chair in Spatial Genome Organization, ran up against a tricky problem trying to detect the directional motion of damaged DNA. (Like many scientists he often uses yeast cells for their similarity to the human genome, their ease of use and low cost.)

Keep in mind the genome is not a static set of biochemical instructions. It exists in a dynamic environment inside the nuclei of our cells – and the action of repair machinery goes into high gear when a piece of DNA is damaged by chemicals or radiation, for example. Understanding these mechanisms can help refine targets for improved cancer therapies.

“If you know that a key step of DNA repair is critical to our ability to treat cancer but you think this step is random, it is hard to design rational, targeted therapeutics or to improve upon our current therapies,” said Mekhail, an associate professor in the Department of Laboratory Medicine and Pathobiology.

Mekhail’s team had previously shown how damaged DNA is transported to specialized parts of the nucleus that act as DNA “hospitals”, areas enriched in DNA repair factors. Transporting the DNA to those areas are motor proteins that act as DNA “ambulances”.

In the new study from Mekhail’s team, first-author and PhD student Roxanne Oshidari used super-resolution microscopy and found that the “ambulances” transport damaged DNA along “highways” that are built on-demand from filamentous proteins called microtubules.

“This was very exciting as it suggested that damaged DNA can exhibit directional motion – not just random mobility as previously thought,” said Oshidari. But the microtubule highways are themselves also moving, making the calculations tricky to separate the motion of the damaged DNA transported by “ambulances” from the oscillating motion of the “highways”. This sent Mekhail on the hunt for the right collaborator.

“We looked across the globe for experts in single particle motion physics and were happy to find that world-renowned experts in that field are actually aerospace engineers here at the University of Toronto Institute for Aerospace Studies,” said Mekhail. He sent an email to Institute Director Christopher Damaren and was delighted with the response.

“Immediately, Chris was highly enthusiastic and demonstrated a true passion for the problem. We had several meetings in which we went over all of the data and brainstormed possible solutions. Side conversations often centered on the similarities and differences between our experience as biomedical researchers and their experience as aerospace engineers specializing in spacecraft motion physics.” Read the full story…