Weizmann Scientists Decode DNA Repair Enzyme Preferences Linked to Mutation Patterns and Cancer

Researchers at the Weizmann Institute of Science have uncovered how key DNA repair enzymes selectively target specific DNA sequences and structures, shedding light on why some mutations persist while others are corrected. Published in Nature Communications, the study led by Dr. Ariel Afek and doctoral student Noga Levi reveals that the enzymes’ preferences influence the human genome’s evolution and may explain cancer development.

DNA mutations often result from unrepaired damage, affecting gene function and contributing to diseases and aging. The team developed a DNA chip containing thousands of short DNA molecules with identical damage but varying surrounding sequences. They found that three major repair enzymes are highly sensitive to the exact base sequence around the damage, even bases located five positions away, and prefer certain structural features such as narrow regions in the DNA helix.

Collaborating with Prof. Brian P. Weiser’s group at Rowan University, the researchers used computer simulations to show that an enzyme’s amino acid scans the damaged site’s environment, attracted to negatively charged narrow DNA regions. They also demonstrated that these enzyme preferences correlate with mutation patterns accumulated over human evolution and in cancer genomes, suggesting that repair efficiency shapes mutation distribution.

Dr. Afek explained that understanding these preferences helps clarify which genomic changes are naturally tolerated and which contribute to cancer when repair systems fail. The findings open avenues for improving gene editing technologies and developing targeted cancer therapies by manipulating DNA repair mechanisms. The study involved additional researchers from the Weizmann Institute and Rowan University and was first published by the Weizmann Institute’s "Scientific Magic Journey" platform.