TNKS1

Tankyrase-1, encoded by the TNKS gene in Homo sapiens, is a member of the poly(ADP-ribose) polymerase (PARP) family. It is a multi-domain enzyme characterized by N-terminal ankyrin repeats, a sterile alpha motif (SAM) domain, and a C-terminal catalytic ADP-ribosyltransferase (PARP) domain. Tankyrase-1 catalyzes the transfer of ADP-ribose units from NAD+ to target proteins, generating poly(ADP-ribose) chains and automodification.

In signaling, tankyrase-1 promotes the degradation of AXIN proteins, scaffold components of the beta-catenin destruction complex. PARylation of AXIN leads to recognition by the E3 ubiquitin ligase RNF146 and subsequent ubiquitin-proteasome–mediated degradation, reducing the destruction complex and stabilizing beta-catenin to activate Wnt target gene transcription. Through this mechanism, TNKS1 is a positive regulator of canonical Wnt signaling in many contexts.

In telomere biology, tankyrase-1 regulates telomere length by PARylating TRF1, diminishing TRF1’s telomeric binding and allowing telomerase access; it also participates in telomere maintenance and genomic stability.

Subcellularly, tankyrase-1 localizes to telomeres and to cytoplasmic structures and, during mitosis, associates with spindle poles and centrosomes. It interacts with several partners, including RNF146, TRF1, and components of the Wnt pathway.

Dysregulation of TNKS1 has been linked to cancer and other diseases, making tankyrase inhibitors a focus of therapeutic research. Small molecules such as XAV939, IWR-1, and G007-LK inhibit the PARP activity or PAR-dependent protein interactions, stabilizing AXIN and suppressing Wnt signaling in preclinical models.