Image of a colorectal cancer cell line in which the gene for DNA repair protein UNG has been knocked out. The cells have been treated with floxuridine and stained to show discrete foci of N6-methyladenosine marks in the nuclei. Image credit: Brooke A. Conti (CC BY 4.0).
All mammals store their genetic material in the form of DNA, which is constantly damaged by factors such as ultraviolet radiation, chemicals, and errors during cellular processes. To prevent such damage from causing harmful mutations, it is important that cells have repair mechanisms that can fix damaged DNA.
Some drugs used to treat cancer cause damage to DNA by incorporating uracil, a compound that doesn’t belong in DNA. This can lead to DNA mutations if not repaired. An enzyme known as UNG2 is involved in repairing this damage by removing the uracil-based lesions. However, the process of uracil repair was not fully understood.
To investigate, Conti et al. treated cancer cells with the drug floxuridine, which is known to cause uracil-based DNA damage. A genetic screening technique identified that a gene encoding an enzyme known as METTL3 is required for repairing uracil-related damage. Further experiments suggested that METTL3 adds markers known as m6A to DNA to help direct repair by UNG2. Inhibiting METTL3 made the cells more sensitive to the drug treatment and reduced the amount of UNG2 at sites of DNA damage.
While m6A marks are known to exist in bacterial DNA, evidence of them in mammalian DNA has been a topic of debate. The findings of Conti et al. suggest that these modifications form in response to DNA damage and help to facilitate repair DNA in mammalian cells. Further research is needed to clarify how METTL3 and m6A marks interact with other DNA repair pathways. Gaining a greater understanding of these repair processes could help future research into strategies to treat diseases driven by DNA damage, such as cancer.
