University of Toronto researchers recently published a study examining the role of the protein Pbp1 in suppressing the formation of DNA-RNA hybrids. The study is authored solely by U of T researchers, including lead author Dr. Karim Mekhail, Canada Research Chair in Spatial Genome Organization. The study is significant for future research in amytrophic lateral sclerosis (ALS) or Lou Gehrig’s disease.
The genetic information in our bodies is carried in our DNA, which is transcribed to RNA and finally translated into making and regulating proteins, which regulate our physiologies, among other things.
During both transcription and translation, various regulatory elements are required that assist our cells in carrying out the processes correctly. Without certain regulatory elements during translation, DNA and RNA sometimes stick together forming DNA-RNA hybrids that do not allow further progression and the complete formation of RNA.
“We think the debris and hybrids are on the same team in a never-ending Olympic relay race,” Mekhail said to U of T News. “Over time there’s a vicious cycle building up. If we can find a way to disrupt that cycle, theoretically we can control or reverse the disease,” he added.
According to the study, “Pbp1 maintains rDNA repeat stability via suppression of RNA-DNA hybrids.” The protein Pbp1, found in yeast, is the ortholog of the Ataxin2 protein found in humans. These proteins function to help curb the formation of DNA-RNA hybrids.
The researchers made a surprising discovery in restricting caloric intake in yeast cells that lack these Pbp1. The yeast cells under the restrictive diet were provided with media containing 0.05 per cent glucose, while those under the control treatment were grown on media containing two per cent glucose.
The original research was conducted on Saccharomyces cerevisiae, a species of yeast. However, the results have life-changing consequences for humans. The protein Ataxin2 is often missing in patients suffering from ALS. Researchers can now focus on specific biochemical, genetic, and physiological pathways that are involved in this neurodegenerative disease.
In addition, Mekhail and his team are now replicating the results they found in yeast in tissue from ALS patients.
Mekhail and his research team are also studying whether dietary restrictions could be of benefit to ALS patients, particularly during early stages of the disease, or for those at risk of acquiring ALS.
Mikhail further noticed that he foresees an impending “revolution” in ALS treatment and beyond, noting that these hybrids have implication for broader disease treatment.