Abstract: Coordination of the cellular response to DNA damage is organised around a set of large multi-domain ‘scaffold’ proteins, including BRCA1, MDC1, 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation and ubiquitylation on other proteins, and are themselves carriers of such regulatory signals. My laboratory is studying how these post-translational modification, especially phosphorylation, provide the signals for assembly of the multi-protein complexes that mediate DNA damage signalling and repair. I will discuss published work on assembly of the DNA damage checkpoint complex, and present new data on a phosphorylation-dependent collaboration between 53BP1 and TOPBP1 that has a major regulatory role in preventing replication in the presence of DNA damage.
Laurence Pearl is Professor of Structural Biology in the Genome Damage and Stability Centre at the University of Sussex, where he was Head of the School of Life Sciences from 2009 to 2017. For the 10 years before that he was Chairman of the Section of Structural Biology at the Institute of Cancer Research in London. His laboratory studies the structural biology of the DNA Damage Response and the HSP90 molecular chaperone system, and seeks to translate these basic studies for the development of new drugs for the treatment of cancer and other diseases. He is a Wellcome Trust Senior Investigator, a Fellow of the Royal Society (FRS), a Fellow of the Academy of Medical Sciences (FMedSci) and an elected member of the European Molecular Biology Organisation (EMBO) and the Academia Europeae. In 2013 he shared the CR-UK Translational Cancer Research Prize (with Paul Workman, ICR) for uncovering HSP90 as a novel target in cancer therapy and for the development of the leading HSP90 inhibitor, AUY922. He was awarded the 2018 Novartis Medal and Prize by the Biochemical Society