Tankyrase, a protein that decorates other proteins with chemical tags, is being studied to understand how it controls cell behaviour and why blocking it with drugs sometimes causes toxic side effects. This matters because tankyrase is a promising drug target for colorectal cancer, fibrosis, and neurodegeneration, but early inhibitors proved too toxic for patients. The problem is that researchers do not fully understand how tankyrase is regulated—it can assemble into long filaments, and its functions extend beyond its catalytic activity. Without this knowledge, interpreting why some inhibitors work and others fail remains guesswork. The team will use cryo-electron microscopy, biochemistry, and genetic tools to map how tankyrase’s filament structure and substrate-binding modules control its activity. If they succeed, drug developers could design safer, more selective tankyrase inhibitors with a wider therapeutic window. This is fundamental science. It will not produce a new drug tomorrow, but understanding tankyrase’s molecular mechanics is the necessary groundwork—much like early work on PARP1/2 eventually led to the PARP inhibitors now used in breast and ovarian cancer.
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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.
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