Dr Sebastian Guettler

ADP-ribosylation is a post-translational modification carried out by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from their cofactor NAD⁺ onto substrates. ADP-ribosylation controls many aspects of cell function, including DNA repair, cell division, telomere maintenance, chromatin dynamics, apoptosis and various signal transduction processes. Given their roles in DNA repair, telomere homeostasis and tumour-suppressive signalling, several ARTs are currently receiving increasing interest as potential targets for cancer therapy.

The human ART family encompasses 17 members (ARTD1-ARTD17) with similarity of their catalytic domains to that of the ADP-ribosylating Diphtheria toxin but of great diversity in their non-catalytic, accessory domains. Different ARTs can either transfer a single unit of ADP-ribose or attach ADP-ribose processively, thereby constructing poly(ADP-ribose) (PAR) chains, which can be of varying length and branch content. This variety in ART enzymes, their distinct substrate specificities and diverse catalysis products account for the wide range of cellular functions ARTs are involved in.

Despite continued progress in understanding this fascinating enzyme family, our knowledge of the biological roles, modes of action and regulation of many ART family members is currently limited. Our research focuses on understanding the regulation of ARTs, their specificity-determining mechanisms of substrate recognition as well as their cellular roles. We use a multi-angled approach that includes biochemistry, structural biology and functional studies in mammalian cells. We are currently particularly interested in Tankyrase, a poly(ADP-ribose)polymerase (PARP) best known as a regulator of telomerase, Wnt signalling and mitotic spindle assembly.

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 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 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 and Cancer Biology at the ICR. His laboratory studies the regulation and cellular functions of ADP-ribosyltransferases, using a combination of biochemistry, X-ray crystallography and cell biology approaches.