Research Interests

For the last 20 years or so our primary interest has been in the significance of phosphorylation as a reversible molecular ‘switch’ for multi-protein complex assembly, with a major focus on signalling events that regulate the response to highly genotoxic double-stranded DNA breaks.

Our work has produced the first structures of 14-3-3 proteins (Cell 1997), FHA domains from Chk2 and its yeast orthologue Rad53 (Molecular Cell 2000 & 2002), the Polo-box domain from human Plk1 kinase (Cell 2003), Mob1-family proteins (Science 2013) and BRCT-repeat domains from human Brca1 and Mdc1 (NSMB 2004 & Cell 2005), all in complex with phosphorylated motifs from interacting partners. These structural firsts include a much anticipated study of the FHA-BRCT-repeat region of the Nbs1 signalling component of the DNA break repair ‘MRN’ complex (Cell 2009), More recently, we have used electron microscopy and ion-mobility mass spectrometry to describe the overall architecture of the core hetero-octameric Brca1-A histone deubiquitinase complex, providing some intriguing insights into substrate binding and mechanisms of phospho-dependent Brca1-mediated regulation (Cell Reports 2016).

Current projects build on and extend these previous studies and include:

• Nbs1 structure-function relationships in interactions with Mdc1 and other factors.
• Structure, assembly and regulation of Brca1 complexes.
• Chk2 kinase activation and identification of novel substrates and effectors.
• New chemical/synthetic biology and mass spectrometry approaches for identification of novel DNA damage-dependent interactions and functional DNA-damage phosphosite annotation.
• Interplay between phosphorylation, ubiquitylation and sumoylation in cell proliferation and apoptosis.