Principle of Damaged DNA Repair Uncovered: "Key to Cancer and Aging Research"

The principle behind the rapid repair of damaged DNA has been uncovered. DNA, often referred to as the "blueprint of life," sustains tens of thousands of instances of damage every day. When such damage accumulates, genomic instability increases, which can lead to cancer and aging. To counteract this, the human body utilizes enzymes that repair DNA damage. A Korean research team has elucidated the pathway by which these enzymes locate areas of DNA damage, thereby maintaining DNA stability. This discovery lays the groundwork for future research related to cancer and aging.

(From the top left) Professor Ja-Il Lee, Department of Life Sciences, UNIST; Professor Kwang-Rok Lee, Department of Life Sciences, KAIST; Professor Je-Joong Yoo, Department of Physics, Sungkyunkwan University; (From the bottom left) Soo-Bin Kim, Integrated Program, UNIST; Dr. Dong-Hoon Lee, KAIST; Kyung-Pil Cho, Integrated Program, Sungkyunkwan University. KAIST

On June 4, KAIST announced that a team led by Professor Kwang-Rok Lee from the Department of Life Science at KAIST, Professor Ja-Il Lee from the Ulsan National Institute of Science and Technology (UNIST), and Professor Je-Jung Yoo from Sungkyunkwan University have identified the molecular mechanism by which the DNA repair enzyme "APE1" (apurinic/apyrimidinic endonuclease 1) locates damaged DNA.

APE1 is an enzyme that recognizes damaged areas of DNA and initiates the repair process. The joint research team tracked the real-time movement of APE1 by combining "single-molecule FRET," which observes the movement and structural changes of individual biomolecules in real time; "DNA curtain," which aligns multiple DNA strands to observe protein interactions; and "molecular dynamics" simulations that calculate molecular movement on a computer.

The results showed that APE1 does not randomly search for DNA damage. Instead, it uses a "one-dimensional diffusion (1D diffusion·DNA)" strategy, moving along the DNA strand to efficiently search for (and locate) damaged sites.

This process is reminiscent of an "intelligent inspection robot" navigating the maze-like underground pipelines of a large city to find tiny leaks. Rather than blindly searching everywhere, APE1 efficiently moves along the "genome highway (DNA)" to locate damage.

AI-generated image. KAIST

Notably, the research team also discovered that the "intrinsically disordered region," a flexible structure at the end of the enzyme, plays a critical role in the DNA search process.

The intrinsically disordered region is a portion of the protein that moves freely without a fixed structure. According to the research team, this region acts like a hook, grabbing onto DNA and keeping APE1 closely attached, enabling it to travel along the DNA for extended periods. In fact, when this region was removed, APE1’s ability to locate damaged sites decreased by more than fivefold.

The study also found that magnesium ions, which are metal ions that facilitate enzyme reactions within cells, are more than just simple cofactors. They serve as key elements that enhance the efficiency of DNA searching. Magnesium ions stabilize the binding between APE1 and DNA, allowing the enzyme to move more efficiently along the DNA strand.

Professor Kwang-Rok Lee stated, "This research is a case in which we have elucidated the mechanism by which biomolecules rapidly search for damaged areas on DNA via the intrinsically disordered region, and then operate precisely through the ordered region. This principle could offer key clues for the development of next-generation anticancer agents that disable the DNA repair function of cancer cells, as well as for research aimed at delaying aging."

Professor Ja-Il Lee emphasized, "This study is significant in that it clarifies the critical role of the intrinsically disordered region in locating DNA damage."

Meanwhile, Dr. Dong-Hoon Lee from KAIST, Subin Kim, a doctoral candidate from UNIST, and Kyungpil Jo, a doctoral candidate from Sungkyunkwan University, participated as co-first authors. The results of this research were published on May 14 in the international journal 'Nucleic Acids Research.'

This content was produced with the assistance of AI translation services.