Findings in a new study by researchers at the University of Toronto challenge a long-held belief that broken DNA moves about randomly within the nuclei of cells and eventually sets off cellular changes.
DNA
In a paper published recently in Nature Communications, scientists revealed that they have found an intricate system that facilitates the repair of defective DNA. Broken genetic material does not always move around aimlessly, their findings show.
Evidence from the study challenges the deep-rooted belief that DNA breaks float aimlessly within cell nuclei. Such breaks, particularly double-strand breaks, constitute a considerable threat to cells.
Karim Mekhail, an associate professor of laboratory medicine and pathobiology at the University of Toronto, had observed that a system featuring filaments, liquid protein droplets, and protein connectors can make DNA repair possible.
Together with his colleagues, Mekhail found in 2015 that proteins can be used to move damaged DNA to areas with high amounts of repair factors – described as DNA “hospitals” – to enable repair.
Cells in the body depend on genome stability to function efficiently and promote overall health. DNA repair is crucial for this stability to be a reality.
This new research was multi-disciplinary, involving biologists, biochemists, and aerospace engineers. The lead author was Roxanne Oshidari, a postdoctoral fellow at U of T.
Exploring DNA repair
Researchers used yeast cells for this new study. The cells that were used had numerous double-strand DNA breaks.
Short microtubule filaments and liquid droplets featuring repair proteins work together to aid and support the process of DNA repair, the team found.
“The liquid droplets work with intranuclear microtubules to promote the clustering of damaged DNA sites,” Mekhail stated. “Repair proteins at these different sites assemble in droplets that fuse into a larger repair-centre droplet, through the action of the shorter nuclear microtubules.”
The research team found that the bigger, oil-like droplet helps to ferry damaged DNA to “hospitals” for repair.
Computer simulations done in collaboration with Nasser Ashgriz, a professor of mechanical and industrial engineering at U of T, helped to shed more light on the repair process.
Surprising discovery
Working with Professor Hyun Kate Lee and Professor Haley Wyatt of U of T’s department of biochemistry, Mekhail carried out diverse tests on the droplets. The tests included bouncing the molecules one against another and then examining their behavior.
The researchers found that the bigger droplets gave rise to an increased number of filament-building blocks after several rounds of droplet fusion. These, in turn, led to something akin to a “self-interlocking brick road” to enable the transport of damaged DNA for repair.
The larger droplet that was formed acted like a spider that produced a web of filaments. These filaments join to longer microtubules, serving as “autobahns” to enable the transfer of broken DNA.
The researchers were quite surprised by this finding.
“It was very bizarre and totally unexpected,” said Mekhail.
He disclosed that it is easy to fail to spot this intricate process. This was mainly because of the considerable automation of imaging in the field. However, software mainly picks up what has previously been detected.
Mekhail said the study showed there was a need to upgrade existing software and to rely more on the human eye. Simulations can be introduced, as necessary, to make things clearer.
References
Oshidari, R., Huang, R., Medghalchi, M. et al. DNA repair by Rad52 liquid droplets. Nat Commun 11, 695 (2020). https://doi.org/10.1038/s41467-020-14546-z
