Future drugs and therapeutic strategies will be designed to target gene regulation. However, understanding the molecular basis underlying gene editing and regulation remains a major challenge. In our lab, we use state-of-the-art computational methods, combining physics, chemistry and computational engineering, to unravel the function and improve application of key macromolecules responsible for gene editing and regulation. Our goal is to provide fundamental knowledge at the molecular level for the treatment of cancer and genetic diseases.
Mechanistic understanding and rational design of CRISPR-Cas9
The field of biology is experiencing a transformative phase, due to the recent discovery of a revolutionary genome editing technology, based on the CRISPR-Cas9 system. Our research aims at unravelling the mechanistic basis and at improving biological applications of this genome-editing machinery. This research is fully integrated with experiments, thanks to the collaboration with Prof. Martin Jinek (University of Zürich) and Prof. Jennifer A. Doudna (UC Berkeley). Our goal is a full mechanistic understanding of CRISPR systems, leading to the design of novel genome editing tools with improved specificity and/or controllable activity.
Nucleosome dynamics and chromatin drug development
The constituents of chromatin, chromosomal DNA and the associated histone proteins, are key molecular targets for anticancer drugs. By integrating MD with X-ray crystallography and biochemical assays in collaboration with Prof. Paul J. Dyson (EPFL), Prof. Curtis A. Davey (NTU-Singapore), we have characterized the mechanism of action of promising metal-based anticancer agents at the level of the nucleosome core particle, the fundamental unit of chromatin. We have clarified the mechanism of action at the molecular level, deciphering the corresponding relationships to cytotoxicity and impact on cancer cell function.
Dissecting the mechanistic basis of non-coding RNA
RNA is a fundamental molecule that codes for protein and controls gene expression, playing a key regulation role in many cell responses and vital processes, such as human genetic heritance and diseases. We are interested in clarifying the molecular basis of non-coding RNA, which regulates gene expression via a variety of yet unknown mechanisms. We have suggested a mechanism for the splicing reaction in the bacterial groupII intron, paving the way for the mechanistic study of the human splicesome.
Catalytic Metals and Enzymatic Processing of DNA & RNA
As originally revealed by Steitz & Steitz (PNAS 1993, 90), DNA/RNA endonucleases perform phosphodiester bond cleavage via a two-metal-ion aided mechanism. I am using computational methods to clarify the two-metal aided mechanism in several endonucleases. My interest in understanding the Steitz & Steitz mechanism started with studies on typeII topoisomerase and other endonucleases.