How do cells limit the harmful effects of naturally occurring DNA damage?

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Because DNA damage can occur naturally, our cells have a variety of mechanisms to limit its consequences. For example, cells can repair the damage or bypass it when making new copies of the DNA. By inactivating the bypass mechanism in mice, researchers from the Garaycoechea group and collaborators were able to study the naturally occurring DNA damage that normally remains largely hidden. They identified specific mutation patterns in the liver and kidney that arise when damage is not bypassed correctly, and discovered that a specific form of DNA repair is normally involved in fixing this type of damage. Their findings were published in Nature Communications.

DNA in our cells is continually damaged, leading to changes in the DNA sequence called mutations. Many mutation patterns have been identified and are linked to diseases like cancer, but the DNA damage that causes them is often unknown.

A great deal of DNA damage occurs through external triggers, like tobacco, alcohol and radiation, but DNA damage can also arise spontaneously in our bodies through byproducts of normal metabolic processes. Juan Garaycoechea and his colleagues are interested in such naturally occurring DNA damage: what different kinds of DNA damage can arise, what causes them, how do they lead to mutations and can this be avoided?

Disabling the protection system

In this new study, a group of researchers led by Yang Jiang applied a clever trick. Normally, the cells in our body can deal with damaged DNA by accurately bypassing the damage when they make new copies of the DNA. This process, called translesion synthesis, requires a special enzyme called polymerase kappa (Polκ). Unlike normal polymerases, Polκ can insert the correct nucleotides opposite damaged DNA bases. This ensures that the damage stays limited to the original DNA strand and is not copied further. The trick used by the researchers? They studied mice that lack Polκ. This allowed them to observe the DNA damage that the translesion synthesis normally prevents from being copied.

Schematic overview of possible responses of the cell to DNA damage. — DNA damage can arise spontaneously through byproducts of normal metabolic processes. Cells have different ways to respond to DNA damage, such as repairing or bypassing it. After repair, the damage is no longer present. During bypass, the cell finds a way to limit the consequences of the damage without removing the damage itself. The Polκ enzyme is involved in lesion bypass. During replication of the damaged DNA, it can insert the correct nucleotides opposite guanine damage. Garaycoechea and his collaborators studied mice without Polκ, in which mutations occur, because the wrong nucleotides are inserted. Credit: Juan Garaycoechea. Copyright: Hubrecht Institute.

New insights

The researchers learned that this damage mostly occurs in the liver and kidney, and specifically on one of the four DNA bases: guanine (G). In addition, the team found out that an additional mechanism, nucleotide excision repair, normally helps mitigate some of this guanine damage. This repair mechanism can remove a DNA segment that contains damage and fill in the gap with the correct nucleotides. In mouse livers that do not have functional nucleotide excision repair, mutations accumulate.

This study identifies previously unknown forms of naturally occurring guanine damage, and shows that two mechanisms collaborate to suppress this type of DNA damage: translesion synthesis and nucleotide excision repair. These findings will help elucidate the causes of naturally occurring DNA damage, and how cells can prevent this damage from leading to mutations.

Publication

Tissue-specific mutagenesis from endogenous guanine damage is suppressed by Polκ and DNA repair. Yang Jiang, Moritz Przybilla, Linda Bakker, Foster C. Jacobs, Dylan Mckeon, Roxanne van der Sluijs, Koichi Sato, Juliëtte Wezenbeek, Joeri van Strien, Jeroen Willems, Alexander E. E. Verkennis, Jamie Barnett, Adrian Baez Ortega, Federico Abascal, Peter W. Villalta, Puck Knipscheer, Inigo Martincorena, Silvia Balbo and Juan Garaycoechea. Nature Communications, 2026.

Juan Garaycoechea is group leader at the Hubrecht Institute