Researcher Unraveling the Secrets of the Human Body… A Breakthrough in Cancer Research Through DNA Damage Repair

The mechanisms by which DNA (deoxyribonucleic acid), the "treasure trove" of genetic information in living organisms, repairs damage are crucial to understanding how the body maintains homeostasis. The human body ensures the accurate replication of genetic information during cell division and restores damaged DNA to its normal state to maintain homeostasis. However, errors that accumulate during this process can lead to diseases such as cancer.

The Center for Genomic Integrity at the Institute for Basic Science (IBS) has identified a new role of the tumor suppressor protein ATAD5, which helps resume normal DNA synthesis even when replication is stalled due to DNA damage. This discovery reveals how the "damage bypass switch" is regulated, providing insight into how DNA replication and damage repair are linked to maintaining genomic integrity.

This research was published in the journal Proceedings of the National Academy of Sciences (PNAS) in August and has gained attention from the academic community for offering a new perspective on understanding diseases such as cancer.

KANG Seok Hyeon, a research fellow at the Center for Genomic Integrity, describes his field as an exploration of how genetic information is preserved in our bodies. While previous studies focused on individual proteins involved in maintaining homeostasis, current research is shifting toward understanding the network of these proteins. We spoke with Dr. Kang about his research and career.

Q. Please introduce yourself.
Hello, my name is KANG Seok Hyeon, and I am a research fellow at the IBS Center for Genomic Integrity, where I lead the Molecular Biochemistry Team. I earned my bachelor's and master's degrees in microbiology from Seoul National University (SNU) and completed my Ph.D. in genetic engineering at the same institution. After working as a research professor at SNU, I conducted postdoctoral research at the Massachusetts Institute of Technology (MIT), studying DNA replication regulation in the Department of Biology. In 2015, I joined the IBS research center.

Q. Please introduce the Center for Genomic Integrity.
Our center aims to elucidate the mechanisms of DNA replication and repair to uncover the secrets of cancer, aging, and human evolution. We conduct research on gene functions related to DNA metabolism and genome editing techniques. The center was established to foster world-class research, attracting scientists from around the globe who study chromosome replication control and DNA damage repair using cellular, biological, and biochemical approaches.

My research specifically focuses on understanding DNA replication and repair mechanisms at the molecular level. Chromosomes can be damaged by natural causes or environmental factors, which can disrupt normal replication and lead to diseases like cancer. Our research seeks to uncover the principles by which cells maintain genetic homeostasis.

Q. What led you to join IBS.
Our research team includes scientists from various countries, including the U.S., Japan, Austria, and Switzerland. Some members were professors at institutions like New York University, while others worked at research institutes such as the Max Planck Institute in Germany.

This international collaboration is possible because research centers like ours, dedicated to genomic integrity, are rare globally. The Korean government’s strong investment in fundamental science has enabled us to establish a focused research group. Some researchers have built their careers here and later moved on to lead world-renowned research teams.

I was drawn to genomic integrity research and joined the center when it was founded, recognizing the potential of Korea’s investment in fundamental science.

Since my undergraduate years, I have been fascinated by how cellular life processes occur at the molecular level. Chromosome replication is a crucial process in cellular life, ensuring genetic information is passed on to daughter cells. This process is tightly regulated to prevent over-replication or under-replication of specific chromosomal regions. My interest in these regulatory mechanisms led me to join the research team.

During my graduate studies, my advisor was conducting research on chromosome replication regulation in E. coli, which intrigued me. While studying prokaryotic cells, I became interested in eukaryotic cells, which are more relevant to human biology. In my postdoctoral research, I studied chromosome replication regulation using yeast proteins, as their replication and repair mechanisms are similar to those in humans. When IBS established the research center, I was excited to join.

Q. What is your main area of research.
I primarily study the biochemical properties of proteins involved in chromosome replication. One key protein in this process is the DNA clamp protein, which has a "closed-ring" structure and must open and close to bind to DNA properly.

In eukaryotic cells, this DNA clamp protein is called proliferating cell nuclear antigen (PCNA), which facilitates DNA synthesis and damage repair. We discovered that the ATAD5 protein prevents PCNA from accumulating excessively on chromosomes, ensuring smooth DNA metabolism.

To investigate the biochemical properties of ATAD5 and its regulatory proteins, we use an in vitro approach, where purified proteins are tested under specific conditions in a controlled environment. We also introduce mutations in specific regions of these proteins to examine how their functions change, helping us understand their structural properties.

Q. Please introduce one of the center’s key research findings.
In August, we published findings demonstrating that ATAD5 regulates the "damage bypass signal," preventing excessive amplification of the signal and maintaining genomic integrity even when DNA damage occurs.

During chromosome replication, PCNA helps DNA polymerase remain attached to DNA. However, when DNA polymerase encounters damaged DNA, it cannot continue synthesis and detaches from PCNA. To prevent replication from halting completely, a small protein called ubiquitin is added to PCNA, signaling for a damage bypass mechanism to activate, allowing replication to continue past the damaged DNA.

However, this bypass process is error-prone and slow, so after the damaged site is bypassed, the ubiquitin signal must be removed to restore normal replication. We identified that ATAD5 plays a crucial role in controlling this process by removing PCNA from DNA and deubiquitinating PCNA to deactivate the damage bypass signal.

Q. What inspired you to pursue this research, and how has the academic community responded.
Genomic damage can result from external environmental factors such as ultraviolet radiation and reactive oxygen species. Additionally, metabolic byproducts within cells can damage chromosomes, and errors during replication can also lead to DNA damage.

Most of these damages are repaired through DNA repair mechanisms. However, if repair fails, chromosomal alterations or mutations can occur, leading to diseases such as cancer. For example, mutations that impair replication regulation or DNA damage repair can cause uncontrolled cell division, contributing to tumor formation.

Previous studies have provided crucial insights into how genomic stability is maintained by demonstrating that ATAD5 regulates PCNA’s DNA binding and activity during DNA synthesis termination and DNA damage bypass signaling, preventing disruptions in DNA replication and repair.

While the activity of ATAD5 had been predicted through cellular and genetic analyses, prediction and experimental proof are not the same. Our research team was the first to experimentally demonstrate that the ATAD5 complex facilitates the removal of PCNA from DNA and promotes PCNA deubiquitination. This discovery was reported to the academic community and has since been widely cited by researchers.

Q. Have you encountered challenges in your experiments.
Biochemical analysis requires the successful purification of target proteins. However, obtaining active proteins and optimizing in vitro assays to measure their activity was challenging. We experimented with different expression systems, including E. coli, yeast, and insect-derived cells, encountering trial and error along the way.

Q. What are your future research plans.
While individual protein functions in DNA replication and damage repair have been studied, there is still much to uncover about how these proteins interact to coordinate cellular functions. I aim to piece together this puzzle.

When DNA replication is hindered by insufficient nucleotide supply or exposure to harmful substances, it causes "DNA replication stress." We have identified several proteins that interact with ATAD5, and we plan to investigate how these proteins regulate ATAD5 activity under normal and stress conditions to maintain genomic stability.

Additionally, we aim to further elucidate the molecular structure of ATAD5 by collaborating with other research teams. In particular, we plan to study the structural properties of the PCNA deubiquitination enzyme complex to better understand its role in chromosome replication and damage repair.