Dr. Tao-shih Hsieh
Institute of Cellular and Organismic Biology
Nankang, Taipei, Taiwan
Fax: (8862)- 2785-8059
Tao-shih Hsieh is Distinguished Research Fellow and Director, Institute of Cellular and Organismic Biology, Academia Sinica, Nankang, Taiwan. He is also Adjunct Professor of Chemistry, National Taiwan University, and Professor of Biochemistry Emeritus, Duke University, USA. Dr. Hsieh grew up and received his formative education in Tainan, Taiwan. He has devoted his effort to the research of fundamental questions in chromatin structure and functions. He has focused his efforts to investigating the mechanism of DNA topoisomerases and their functions in chromatin dynamics. His work characterized biochemically and biophysically eukaryotic type II DNA topoisomerases from human and Drosophila, providing a mechanistic basis for the induction of DNA breaks by many clinically useful anticancer drugs. He is Academician of the Academia Sinica, and Fellow in TWAS (The World Academy of Sciences), and among others, he received the American Cancer Society Junior Faculty Research Award, and served on many advisory boards including US NIH Molecular Biology and Molecular Genetics Study Sections.
His key research areas: DNA structures, chromatin dynamics, DNA topoisomerases, DNA replication, repair and recombination.
The well-known structure of DNA double helix provides an elegant mechanistic basis for storage and transmission of genetic information. However, the unwinding and rewinding of the duplex during the processes of DNA transactions can lead to topological entanglements that result in genome instability if left unresolved. Many other processes during DNA transactions including helical tracking and coiling of DNA to form higher order structures can also lead to topological complexities that are potentially deleterious to cells. DNA topoisomerases are nature's tools to resolve the problems of DNA entanglements by enabling topological transformations, thus regulating the structures of DNA/chromosomes and their associated cellular functions. The importance of these enzymes is also evidenced by the fact that they are ubiquitous in nature and their impairment due to genetic mutations results in deleterious effects including lethality in many organisms.
Topoisomerases tackle these seemingly complex problems by utilizing a simple yet elegant chemistry of reversible transesterification reactions. The active site tyrosine in these enzymes functions as a nucleophile to generate a transient break serving as DNA gate through which all topological transformations can occur. Our laboratory has generated fluorescence-labeled DNA substrate so that we can monitor the strand break and gate opening by topoisomerase using either single molecules measurements or under bulk conditions. These optical approaches to examine the steps in manipulating DNA structures by the enzyme have allowed us to design a facile high through-put screening platform for identifying potential anticancer drugs targeting DNA topoisomerases.