The highly conserved Wnt/ß-catenin signalling pathway plays major roles in stem cell maintenance, embryonic development and tissue homeostasis. Mutations in components of this pathway, particularly the tumour suppressor adenomatous polyposis coli (APC) but also ß-catenin, cause the vast majority of colorectal cancers (CRCs), giving rise to unbridled ß-catenin levels. These oncogenic mutations impair the function of the multi-protein ß-catenin destruction complex, which normally achieves the sequential phosphorylation and ubiquitylation of ß-catenin to trigger its proteasomal degradation, thereby limiting the availability of transcriptionally active ß-catenin. The poly(ADP-ribose)polymerase (PARP) enzyme tankyrase modifies the central destruction complex scaffold AXIN1/2, thereby either impeding destruction complex formation and function or promoting the Wnt-induced inactivation of the destruction complex. Tankyrase thus acts as a rheostat to tune the sensitivity of Wnt-responsive cells to Wnt stimulation. Tankyrase inhibition is being explored as a potential anti-cancer strategy. In our laboratory, we use in-vitro approaches, mainly biochemistry, biophysics and structural biology, complemented with cell biology, to understand the mechanisms of Wnt/ß-catenin signalling and telomere maintenance, and how both of these cancer-relevant processes are controlled by tankyrase. I will present recent insights into the molecular mechanisms of tankyrase, progress in developing novel approaches to inhibit both catalytic and non-catalytic functions of tankyrase and the in-vitro reconstitution of normal and oncogenic Wnt/ß-catenin signalling processes.
Dr Sebastian Guettler studied Biology, Molecular and Cell Biology and Biochemistry at the Universities of Jena and Heidelberg (Germany) and undertook his MSc research with Dr Giulio Superti-Furga at EMBL. For his PhD project, Sebastian joined Dr Richard Treisman’s laboratory at the London Research Institute of Cancer Research UK (now part of the Francis Crick Institute) where he studied how actin controls MRTF-A, a transcriptional coactivator of Serum Response Factor (SRF). For his postdoctoral research, he joined the laboratories of Dr Frank Sicheri and the late Dr Tony Pawson at the Samuel Lunenfeld Research Institute in Toronto. There, Sebastian uncovered the structural basis of the substrate targeting mechanism to the poly(ADP-ribose)polymerase tankyrase, thereby enabling the successful prediction of novel tankyrase substrates and explaining why mutations in the adaptor protein 3BP2 cause cherubism, a rare human disease.
In October 2012, Sebastian joined the Divisions of Structural Biology and Cancer Biology at the ICR. His laboratory studies how ADP-ribosylation regulates cell signalling, in particular Wnt/ß-catenin signalling and telomere homeostasis, using a combination of biochemistry, structural biology and cell biology approaches. Dr Guettler gained the title of Reader at the ICR in 2019.