National Yang Ming Chiao Tung University Structural Biology Team Resolved Drug Resistance of Cancer Cells

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Associate Professor Hsiao Yu-Yuan and his research team

The structural biology team of the College of Biological Science and Technology, National Yang Ming Chiao Tung University (NYCU) adopted the x-ray protein crystallography method to analyze the structure of the apurinic/apyrimidinic endonuclease 1 (APE1)–DNA complex. The team’s goal was to understand how the APE1 protein activity in the human body is utilized by cancer cells to repair their DNA damaged by drugs, thereby developing drug resistance toward DNA-damaging anticancer drugs. In the future, if structure-based drug design can be used to block the activity of APE1, then part of the drug resistance problems of cancer cells can be resolved.

This 3-year research was led by the associate professor Hsiao Yu-Yuan of the Institute of Molecular Medicine, School of Life Sciences, and the experiments were jointly performed by Ph.D. student Liu Tung-Chang, master’s student Lin Chun-Ting and Kuo Kai-Wei, and undergraduate seminar student Chang Kai-Cheng. The project was also a cooperation with professor Chu Jhih-Wei of the Institute of BioMedical Informatics. This groundbreaking result was published in the international top journal Nature Communications and received enthusiastic attention.

APE1 protein is capable of redox as well as and endo- and exonucleolytic cleavage of DNA, features that are related to cancer cell proliferation and drug resistance. Some anticancer drugs can kill cancer cells by damaging the DNA of cancer cells or directly embed in the DNA of cancer cells to block their DNA replication. Cancer cells may also use the DNA repair ability and exonucleolytic cleavage activity of APE1 to mend their DNA or to remove the anticancer drugs embedded in their DNA, rendering some of the anticancer drugs ineffective. However, the mechanism of APE1 protein’s DNA exonucleolytic cleavage activity is still unclear. Therefore, the structural biology team of NYCU used the x-ray protein crystallography method to analyze several APE1–DNA complexes. Together with enzyme activity analysis, their study systematically constructed the DNA exonucleolytic cleavage activity molecule mechanism of APE1, providing a substantial understanding of the DNA cleavage mechanisms of APE1 protein. In the future, these APE1 protein structures can be used to develop small molecule inhibitors to fight the drug resistance problem of cancer cells.

Associate professor Hsiao maintained that in addition to having the Ministry of Science and Technology Young Scholar Fellowship—Grant for the Columbus Program as the major funding, their study was also made possible by the hardware provided by the College of Biological Science and Technology, NYCU, such as the newly completed Biomedical Engineering Building—Hsien-Chi Building, and the research bonds and equipment offered by the two research centers of NYCU. He believed that the merging of National Yang Ming University and National Chiao Tung University will facilitate the production of more favorable research results in the future.