ICF: Molecular mechanisms of the ADP-ribosyltransferase tankyrase in normal and disease signalling

ADP-ribosyltransferases (ARTs), which catalyse a post-translational modification known as ADP-ribosylation, consuming nicotinamide adenine dinucleotide (NAD+), have emerged as important drug targets in a range of pathologies. The most prominent examples are the DNA damage sensors PARP1 and PARP2, targets of clinical PARP inhibitors in breast, ovarian and prostate cancer1,2. Yet, the actionable repertoire of ARTs extends to other family members. Tankyrase (TNKS, TNKS2) is a highly conserved, versatile ART which like PARP1/2 catalyses the attachment of chains of poly-ADP-ribsose (PAR) to substrates. Tankyrase controls a variety of physiological processes, including Wnt/beta-catenin signalling, Hippo signalling, telomere length regulation and glucose homeostasis, with disease links to cancer, diabetes, fibrosis, neurodegeneration and anti-viral responses3,4. Inhibition of Wnt/beta-catenin signalling, relevant to drug development efforts to target colorectal cancer, fibrosis and neurodegeneration, is largely attributable to the stabilisation of the tankyrase substrate AXIN1/2, a key negative regulator of the pathway5. Initial tankyrase inhibitor studies indicated a small therapeutic window, common for agents targeting the Wnt/beta-catenin pathway6,7. Whilst the mechanism of toxicity remained unclear, new compounds show much-reduced toxicity, rekindling drug development efforts8,9. Notwithstanding, our knowledge of tankyrase's regulation and mechanism of action still lags that of PARP1/2, which complicates the interpretation of inhibitor responses and limits further inhibitor development. Open questions include the mechanisms of tankyrase regulation by self-assembly into filaments and other inputs, the precise mechanistic impact of catalytic inhibitors, and the roles of catalytic vs. non-catalytic functions5,10.

We have a long-standing interest in tankyrase, having revealed substrate binding and polymerisation mechanisms, catalysis-independent (scaffolding) functions and initial approaches to target these5,10-14. Our recent cryo-electron microscopy (cryo-EM) study revealed the architecture of part of the tankyrase filamentous polymer, providing important mechanistic clues10. As the substrate-binding modules were absent from this study, their contribution to tankyrase regulation, which our preliminary structural, biochemical, biophysical, genetic and proteomic studies point towards, remained unclear.