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Scientists at the Peter MacCallum Cancer Center have uncovered new insights into how cells regulate DNA methylation, a fundamental process that helps keep potentially harmful viral elements in our genome under control.
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DNA acts as the body's instruction manual, guiding how cells grow, develop and function. Human DNA contains around 20,000 genes, which make up about 2% of the genome. In contrast, more than half of our DNA consists of ancient viral sequences that entered the human genome millions of years ago during evolution.
To keep these viral elements silent, cells rely on a process called DNA methylation. This involves attaching small chemical tags to specific regions of DNA, acting like a "do not disturb" signal. These tags attract proteins that tightly pack the marked DNA, making it harder for the cell to read and preventing harmful viral sequences from becoming active.
The new research from Peter Mac focused on understanding how the key enzyme responsible for maintaining these chemical tags, known as DNMT1, is regulated within cells. Clinician-scientist Dr. Jesse Balic, who co-led the study published in Nature Genetics, said while DNMT1 has been studied for a long time, important questions remained about how its activity is controlled.
"We have known for decades that DNMT1 maintains these chemical tags, and more recently we have also become aware that abnormalities in the function of DNMT1 can lead to a variety of human diseases, including cancer," Balic said.
"However, what we didn't fully understand was exactly how DNMT1 activity is controlled in a cell. Given its role in cancer and other diseases, learning how we can precisely manipulate this enzyme could provide new avenues for treatment."
The team found that when DNMT1 activity is blocked using specific drugs, DNA methylation levels decrease and previously silent viral regions of the genome become active again.
Peter Mac laboratory group leader Professor Mark Dawson said this reactivation causes cells to behave as though they are under viral attack. "When we block DNMT1 with a drug, DNA methylation is lost and these ancient viral areas become active again," Dawson said. "Even though there is no real virus present, the cell acts as if it is under attack, triggering an internal antiviral response that can lead to cell death.
"If we understand this process in detail, we may be able to tailor this response to cancer cells so that we can selectively kill them."
Dawson said the findings revealed previously unknown regulators that help maintain DNA methylation and genome stability. "We are excited that our fundamental discovery science research has identified new regulators responsible for maintaining DNA methylation and genome stability," he said.
"This knowledge provides important insights that may guide future therapeutic interventions for the treatment of cancer and other human diseases. Importantly, because most plants and animals also use DNA methylation, this research may have implications beyond medicine, including in agriculture and farming."
More information: Brian J. Liddicoat et al, SUMOylation enhances DNMT1 function to repress mega-intergenic RNAs and viral mimicry, Nature Genetics (2026). DOI: 10.1038/s41588-026-02664-1
Provided by Peter MacCallum Cancer Centre
This story was originally published on Phys.org.
