Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2) (TNKS1/2)

Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2), also known as PARP5a and PARP5b, are enzymes belonging to the poly(ADP-ribose) polymerase family that catalyze the transfer of ADP-ribose units onto target proteins (UniProt O95271, Q9H2K2). They play a critical role in the canonical Wnt/beta-catenin signaling pathway by PARsylating AXIN, a scaffold protein in the beta-catenin destruction complex, leading to its ubiquitination and proteasomal degradation (PubMed: 19759582). This process facilitates the stabilization and nuclear translocation of beta-catenin, driving the expression of genes involved in cell proliferation and survival. Additionally, tankyrases regulate telomere length by PARsylating TRF1, releasing it from telomeric DNA to allow access for telomerase (PubMed: 9843510). Due to their role in promoting oncogenic Wnt signaling, tankyrases are major therapeutic targets in cancers such as colorectal, breast, and lung cancer (PubMed: 32824158). Small-molecule inhibitors targeting the catalytic PARP domain of TNKS1/2 have shown efficacy in preclinical models, though clinical progression is often hindered by gastrointestinal toxicity due to the essential role of Wnt signaling in intestinal stem cell maintenance (PubMed: 27535974).

Other names

TNKS1TNKS2PARP5aPARP5bARTD5ARTD6Tankyrase-1Tankyrase-2Poly [ADP-ribose] polymerase 5APoly [ADP-ribose] polymerase 5B

Inhibition of the catalytic PARP domain to prevent the PARsylation of substrate proteins such as AXIN, which stabilizes the beta-catenin destruction complex and leads to the degradation of beta-catenin.