To prevent the development of cancer, the body relies on tools including the ability to “turn on” silenced genes that, once activated, can suppress tumors. Scientists have discovered a mechanism behind this ability that suggests the possibility of new therapies that would activate silenced genes when the body’s normal process fails.
Researchers led by geneticist Alfonso Bellacosa investigated a process called methylation, in which a cell chemically “tags” specific genes to turn them off. The cell silences the genes by adding a chemical compound known as a methyl group to their DNA; without the methyl group, the genes remain active.
Scientists take great interest in methylation, Bellacosa explains, because it is a key part of normal gene regulation—but when it goes awry and silences genes that normally suppress tumors, cancer results. Indeed, some cancer drugs work by demethylating, and thereby reactivating, silenced genes. But those drugs demethylate multiple genes, not just those involved with cancer, which causes side effects and other problems.
In a study published in June in the journal Cell, Bellacosa and his team present new clues to how demethylation works. The researchers discovered that a protein called thymine DNA glycosylase, or TDG—known to help repair DNA—is also responsible for removing methyl groups from DNA. The researchers found that in mice that lacked TDG activity, methylation was amiss—genes that normally would be demethylated weren’t and instead remained silenced.
“Since we now know there are proteins that actively affect demethylation, we can imagine a new type of cancer therapy that would demethylate only specific genes and not any others,” Bellacosa says. “We would have a more precise, more targeted type of therapy.”
Also exciting, he adds, is the discovery that cells use tools that normally repair DNA for a very different purpose: the reversal of gene silencing by demethylation. “We may be several years away from taking full advantage of this new knowledge,” he says. “But we will get there.”
The study was supported by grants from the National Institutes of Health.