Researchers at Karolinska Institute and SciLifeLab in Sweden report they have improved the ability of a protein to repair oxidative DNA damage and created a new protein function. Their new technique can lead to improved drugs for diseases involving oxidative stress, such as cancer, Alzheimer’s disease, and lung diseases.
Their findings are published in the journal Science in a paper titled, “Small molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.”
“Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair,” wrote the researchers. “Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function.”
The researchers sought to improve the function of OGG1, an enzyme that repairs oxidative DNA damage, implicated in aging and diseases such as Alzheimer’s disease, cancer, obesity, cardiovascular diseases, autoimmune diseases, and lung diseases.
The team used a method called organocatalysis, a tool developed by Benjamin List and David W.C. MacMillan. The researchers examined how such catalyst molecules, previously described by others, bind to OGG1 and affect its function in cells. One of the molecules proved to be of particular interest.
“When we introduce the catalyst into the enzyme, the enzyme becomes ten times more effective at repairing oxidative DNA damage and can perform a new repair function,” said the study’s first author Maurice Michel, PhD, assistant professor at the department of oncology-pathology, Karolinska Institute.
The catalyst made it possible for the enzyme to cut the DNA in an unusual way so that it no longer required its regular protein APE1 to work but another protein called PNKP1.
The researchers believe that OGG1 proteins improved in this way can form new drugs for diseases in which oxidative damage is implicated.
“We believe that this technology could instigate a paradigm shift in the pharmaceutical industry, whereby new protein functions are generated instead of being suppressed by inhibitors,” said Thomas Helleday, PhD, Karolinska Institutet. “But the technique isn’t limited to drugs. The applications are virtually unlimited.”