Development of cancer is generally due to errors that occur in cellular pathways. The Sixma lab uses structural biology to understand these errors at the atomic level. They use a combination of cryo-EM and X-ray methods, to provide three-dimensional structures and interpret structural data using a variety of biochemical and biophysical approaches. These studies provide mechanistic insight in the molecular processes and they provide targets for drug design studies.
The main focus of the lab is on mechanisms of ubiquitin conjugation and deconjugation in processes involved in the regulation of genome maintenance. The importance of ubiquitin modification as a signaling system in DNA damage response and in transcriptional regulation has become clear. The Sixma lab uses biochemistry and structural biology to address mechanistic questions for two important cellular targets, H2A and PCNA. In these cases, site-specific targeting by selective E3 ligases result in different cellular signals. Particular focus is on site specificity and chain formation by the ligases and the regulation and selectivity of deubiquitinating enzymes. The relevance of deubiquitinating enzymes for critical genome maintenance pathways makes them interesting as possible drug targets. The detailed analysis of the regulation of these DUB enzymes will aid the drug discovery research. These analyses identify allosteric sites that may be targeted and they are important in understanding the modes of action of possible compounds.