KAIST uncovers how DNA repair enzyme hunts down damage at high speed

Human DNA sustains roughly 10,000 to 20,000 instances of damage per cell every day. Left unaddressed, such damage can lead to cancer, accelerated aging and other life-threatening conditions — making precise detection of even the smallest lesions essential.

South Korean researchers have uncovered the mechanism by which a DNA repair enzyme slides along the DNA strand to locate damaged sites at extraordinary speed.

KAIST announced Thursday that a team led by professor Lee Kwang-rok of its Department of Biological Sciences, working with professor Lee Ja-il of UNIST and professor Yoo Je-joong of Sungkyunkwan University, has identified the precise molecular mechanism by which the DNA repair enzyme APE1 detects damaged DNA.

The research team tracked APE1's movement in real time and found that the enzyme does not search DNA randomly. Instead, it employs a "one-dimensional diffusion" strategy, sliding along the DNA strand to locate damaged sites.

The process resembles an intelligent inspection robot navigating a labyrinthine network of below-ground pipes beneath a vast city, moving methodically to pinpoint microscopic leaks rather than searching at random. APE1 travels efficiently along what the researchers describe as a "genomic highway," rapidly zeroing in on sites of damage.

The team also found that a flexible structure at the enzyme's tail end — known as an intrinsically disordered region — plays a central role in the search process. This region acts like a hook, keeping APE1 anchored to the DNA strand so it can travel along it for extended periods without detaching. When the researchers removed the region, the enzyme's ability to locate damaged sites fell by more than fivefold.

The team also confirmed that magnesium ions — metal ions that assist a range of enzymatic reactions inside cells — do more than serve as a simple cofactor. They stabilize the bond between APE1 and DNA, enabling the enzyme to move along the strand more effectively and boosting overall search efficiency.

"By blocking APE1's damage-search pathway, it becomes possible to develop a new treatment strategy that disables cancer cells' self-repair capacity," said Lee Kwang-rok, the KAIST professor who led the study. "The findings can also provide important clues for research into aging-suppression strategies and the treatment mechanisms of intractable diseases caused by genetic mutations, by drawing on the principles that maintain genomic stability."

Lee Ja-il of UNIST said the findings carry significant weight because they demonstrate that the intrinsically disordered region — which moves flexibly without a fixed structure and interacts with a wide range of molecules — plays a key role in locating sites of DNA damage.

The findings were published in the international journal Nucleic Acids Research on May 14.