Grant: Project Grant

Poly(ADP-ribose) polymerases (PARPs) create the posttranslational modification poly(ADP- ribose) to regulate a wide variety of cellular programs, such as DNA damage repair, gene transcription, cell death signaling, and metabolism. The PARP superfamily has 17 members with a diverse set of regulatory domains attached to the conserved catalytic domain that creates the ADP-ribose modification. A more detailed understanding of the specific biological pathways regulated by PARPs has emerged recently. However, there remain fundamental gaps in our knowledge of how the catalytic activities of the different PARP family members are regulated, and this limits our understanding of how several important cellular programs are regulated by ADP-ribosylation. Tankyrase is a PARP enzyme that is involved in a number of cellular pathways, including telomere maintenance, glucose homeostasis, Wnt signaling, mitotic progression, and RNA processing. How tankyrase selects cellular target proteins for modification is poorly understood, in part due to limited structural information, and in part due to a paucity of biochemical analysis. Based on our preliminary structural and biochemical work, the proposed studies will provide important advances in our understanding of how tankyrase selects and modifies target proteins. Several PARP enzymes, including tankyrase, are the targets of small-molecule inhibitors used for the treatment of cancer. Current PARP inhibitors lack isozyme specificity and are therefore limited in their ability to serve as specific biological probes of PARP function. The proposed studies will build toward a mechanistic understanding of tankyrase activity and regulation that will contribute to the design of tankyrase-specific inhibitors as chemical probes, and potentially as new anti-cancer compounds.