Yuk-Ching Tse-Dinh conducted her PhD thesis research in the laboratory of Professor James C. Wang, who discovered the ubiquitous class of enzymes, DNA topoisomerases, as master manipulators of genomes. She identified tyrosine nucleophile as the active site function for the cutting-rejoining of DNA and the formation of the covalent phosphotyrosine linkage in the covalent intermediate formed between topoisomerase enzyme and cleaved DNA. The topoisomerase covalent intermediates, while essential for topoisomerase functions, can also turn into lethal poisons for the cell if trapped by therapeutic drugs or environmental toxins, resulting in DNA lesions and cell death.

Every bacterial pathogen has at least one type IA topoisomerase, providing a target for discovery of new antibiotics to combat multi-drug resistant infections, including MDR and XDR-TB. The study of the structure, mechanism and physiological functions of bacterial topoisomerase I provide the basic foundation for translational application of this enzyme as a novel antibacterial target. Drug discovery research extends to anticancer drugs targeting human DNA topoisomerases. The control of DNA structure by DNA topoisomerases can affect stress response and genomic stability, with implications for bacterial pathogenesis, aging and cancer.

Current research areas of interests include: (i) Development and implementation of cell based and enzyme based HTS assays to identify topoisomerase inhibitors; (ii) SAR and optimization of topoisomerase inhibitor structures to generate specific antibacterial or anticancer drug leads; (iii) Structural and biochemical studies of type IA topoisomerases to elucidate the mechanism of DNA manipulation and inhibitor action; (iv) Topoisomerase DNA-protein and protein-protein interactions during stress challenge from bacteria to mammalian systems.