DNA repair enzymes favor specific sequences, shaping mutation patterns in the human genome

When a wound fails to heal, it often leaves a scar, much like how mutations—permanent alterations to the genetic code—result from DNA damage that hasn't been effectively repaired. These mutations can impair gene function, contribute to disease, and drive aging, but they also introduce genetic variation that fuels evolution. However, scientists are still unclear on why some damaged DNA regions are repaired while others remain unrepaired.

In a study published in Nature Communications, researchers from the Weizmann Institute of Science have identified which DNA sequences and structures are favored targets for several critical DNA repair enzymes. Dr. Ariel Afek's lab found that the preferences of these enzymes have shaped the human genome and may even help explain how cells become cancerous.

Every day, thousands of chemical reactions occur in living cells, damaging the genome. DNA repair systems can generally fix most of the damage, but not all of it. The rate at which mutations accumulate is determined by the balance between the rate of damage and the rate of repair, which varies across different parts of the genome.

The team developed a chip with thousands of DNA fragments carrying the same damage but different sequences to study where the repair enzymes were most and least effective. They discovered that repair enzymes' effectiveness is influenced by the sequence of genetic bases surrounding the damage site. One enzyme, in particular, prefers sequences that create a narrow region in the helical DNA structure.

To understand why, the scientists collaborated with researchers at Rowan University, who used computer simulations to show that an amino acid in the enzyme is attracted to the negative electrical charge found in narrow DNA regions. They also found that regions where this repair enzyme works efficiently retain more C bases, while other regions see an accumulation of unrepaired changes.

This finding could help explain human evolution, as regions with efficient repair mechanisms may accumulate C bases that help organisms adapt to changing environments. Additionally, the study revealed a correlation between the repair enzymes' preferences and mutational signatures found in human tumors, suggesting that repair enzyme efficiency may influence cancer development.

Understanding how DNA repair mechanisms choose their target sites could lead to better gene editing tools and potentially new therapies for cancer, as failures in repair mechanisms are a major driver of the disease.