Laurence Pearl - Overview

Since moving to the Chester Beatty Laboratories of the Institute of Cancer Research (ICR) in September 1999, my group has focused on structural and biochemical studies of proteins and complexes of importance in the aetiology and treatment of cancer. My research activities and personnel at the Chester Beatty Laboratories can be subdivided in to three main biological areas: (1) DNA Damage Recognition, Signalling and Repair; (2) Signal Transduction and Transcriptional Regulation; and (3) Chaperone Mediated Protein Activation. In the DNA repair field, we are studying the detailed processes of recognition and base excision repair of altered and mismatched bases by DNA glycosylases. We are also studying the recognition and repair of gaps, nicks, breaks and complex structures in DNA by a variety of repair and recombination enzymes, and some of the downstream signals that these repair events generate. Our studies of signal transduction and transcriptional regulation are focused on scaffold-mediated protein kinase specificity, particularly in the carcinogenic Wnt-signalling pathway, and on the regulation of gene expression by co-repressors such as Gro, and by repression effectors that covalently modify chromatin. Our molecular chaperone studies are primarily directed at understanding the structure and mechanism of Hsp90, which is the central player in a dynamic series of multi-protein complexes with key roles in activation and regulation of important cell regulatory pathways that are frequently misregulated in cancer. We are also studying the large CCT complex which acts as a specific chaperone for cytoskeletal proteins such as actin and tubulin. In all these studies we are seeking to obtain insights into the structural basis for the biological phenomena and particularly to understand the specificity of the macromolecular interactions involved, with the aim of using this knowledge to assist the development of new, target-directed anti-cancer therapies.