New enzyme reveals where and how often DNA damage occurs

As we live longer, the number of cancer patients continues to increase. The World Health Organization estimates that in 2022 alone, 20 million people developed cancer, and that every fifth person is expected to receive a diagnosis during their lifetime. Cancer is caused by changes – such as mutations – in the cell’s DNA, which in turn arise as a result of damage to our DNA. Science has long tried to develop a tool to determine exactly where in the DNA single-strand breaks have occurred, and now researchers at Uppsala University are launching a method that enables this and to determine whether chemicals cause DNA damage.

“Our method is based on the new artificial and error-prone enzyme, Sloppymerase, binding to single-strand breaks in DNA and repairing the damage by incorporating wrong nucleotides – the building blocks that store and transmit genetic information, and thereby creating a unique signature that can be identified with all available sequencing technologies. With this method, we have studied where single-strand breaks in DNA occur and also been able to conclude that every cell contains an average of approximately 5000 single-strand breaks,” says Leonie Wenson, PhD Student at the and first author of the article.

Single-strand breaks are enriched in the promoter region of active genes with potential significance in preparing DNA for transcription – the process where genetic information from DNA is copied into an RNA molecule. The article also shows that the DNA-binding drug BMH-21 inhibits the formation of DNA single-strand breaks, thereby also leading to a decrease in the transcription.

“We hope that our method will enable new cancer treatments with drugs that prevent DNA single-strand breaks in selected genes, thereby switching off the genes that the cancer cell is dependent on. Our article in Nature Communications is the result of seven years work, with a number of international partners contributing invaluable input, and that is already opening several scientific doors,” states Leonie Wenson.

Sloppymerase offers numerous areas of application: Within life sciences, the enzyme gives hope for new knowledge about basically all diseases caused by incorrect gene expression. Its capacity to identify and analyze induced DNA damage can enable and accelerate more reliable identification of toxic chemicals. Ola Söderberg's team is currently researching Sloppymerase’s potential in various molecular biology methods, while in parallel preparing a study to use their polymerase to identify the enzymes that cause DNA strand breaks.

“From day one, our ambition has been that the outcome of this work will benefit society and in 2023 we received the UU Innovation Attractive Innovation Award. The same year, Genovis took over the IP rights to Sloppymerase and is now working to commercialize the enzyme. Our team has discovered several important clues to how transcription is regulated. Knowledge that in the long term might play an important role for new and more effective cancer treatments,” says Ola Söderberg, Professor of Pharmaceutical cell biology.

text: Magnus Alsne, photo: Mikael Wallerstedt