Dr. Pascal studies the structure and function of macromolecular complexes to provide detailed mechanistic insights into cell biology. A major focus of his research is trying to understand the structure and the function of proteins involved in DNA repair. The DNA of our cells is frequently damaged due to environmental agents and errors in the process of genome replication. Various cellular mechanisms allow the repair of damage and the maintenance of genome integrity, which is critical to prevent cellular transformation and cancer.
Dr. Pascal's research focuses on proteins involved in DNA repair, including the poly(ADP-ribose) polymerase, or PARP family of enzymes and DNA ligases. PARPs play critical roles in maintaining genome integrity by recognizing and binding to breaks in the DNA. This allows the subsequent recruitment of a variety of factors that will work to repair the damage such as the DNA ligases that will work to seal the break at the end of the repair process.
Dr. Pascal uses a structural biology approach to study the function of PARPs, DNA ligases and other proteins involved in DNA repair. One of the main techniques used by the Pascal laboratory is x-ray crystallography, which allows one to obtain a high resolution three-dimensional image of protein complexes. In the past, this technique was used by the Pascal laboratory to obtain the first model of PARP-1 and of DNA ligase I each bound to a broken DNA fragment.
These results have allowed a better understanding of how these proteins work to perform their cellular functions. Recently, PARP inhibitors have emerged as promising therapeutics for the treatment of inflammation and cancer. Dr. Pascal's group uses his expertise in structural biology combined with high-throughput screening to identify new inhibitors of PARPs and other DNA repair proteins for cancer and other disease treatments.