Leroy F. Liu, Ph. D.
1. The repair of topoisomerase cleavage complexes. Studies conducted in Dr. Liu’s laboratory have led to the discovery of topoisomerases as major molecular targets for a number of highly effective antitumor agents. These antitumor drugs kill tumor cells through trapping of covalent reaction intermediates, termed the cleavable or cleavage complexes. In addition to antitumor drugs, DNA structural modifications (e.g. abasic sites, UC adducts, oxidatively damaged DNA and etc.) and cellular stresses (e.g. pH and thiol stresses) have also been shown to trap topoisomerase cleavage complexes. This laboratory is currently involved in studying the molecular pathways involved in processing and repair of topoisomerase cleavage complexes.
2. The ubiquitin-like protein, ISG15, in tumorigenesis and drug sensitivity. We have recently demonstrated that the ubiquitin-like protein, ISG15 (Interferon-Stimulated Gene 15) is highly elevated in tumor cells. In addition, we have shown that ISGylation in tumor cells inhibits the ubiquitin/26S proteasome pathway. The significance of elevated expression of ISG15 during tumorigenesis is being investigated in the context of tumor microenvironment, immune modulation and drug sensitivity.
3. The molecular basis for aging. We have demonstrated that RNAi-mediated knockdown of either atg-7 or atg-12 results in lifespan shortening of both wild type and daf-2 mutant C. elegans, suggesting that autophagy is important for aging regulation. We have also demonstrated that AMPK regulates mitochondrial biogenesis and turnover. In addition, we are also investigating the role of ROS in telomere-initiated cell death as well as its implication in neuron degeneration and aging regulation.
4. G-quadruplexes and G-quadruplex stabilizers. G-quadruplexes (GQs) are four-stranded nucleic acids that consist of successive G-G-G-G quartets (G-quartets). The importance of GQs as biologically-relevant nucleic acid structures is emerging. Such structures have been postulated to exist in human telomeres, promoter regions of some oncogenes and various RNAs. Most significantly, synthetic GQs have been shown to be highly effective in inducing apoptosis in tumor cells, and cause regression of breast tumors in mouse xenograft models. In addition, telomestatin, a highly specific GQ stabilizer, has been shown to exhibit antitumor activity in mouse xenograft models. In collaboration with Drs. Edmond LaVoie, Joseph Rice, Haiyan Qi, and Daniel Pilch, we have initiated a program aimed at developing GQ stabilizers and GQ-folate conjugates as novel anticancer agents.