TNKS

TNKS, short for tankyrase, refers to two closely related human enzymes: tankyrase-1 (TNKS) and tankyrase-2 (TNKS2). They are members of the poly (ADP-ribose) polymerase (PARP) family and catalyze poly(ADP-ribosyl)ation of substrate proteins using NAD+ as a donor. The proteins feature ankyrin repeats for substrate recognition and a catalytic PARP domain responsible for PAR synthesis. They localize to multiple cellular compartments, including the cytoplasm and the Golgi apparatus, and can associate with mitotic spindle structures during cell division.

TNKS proteins regulate a variety of cellular processes, most notably Wnt/β-catenin signaling. By PARylating AXIN1 and AXIN2, tankyrases promote the degradation of AXIN and disassembly of the β-catenin destruction complex, leading to stabilization and nuclear translocation of β-catenin and activation of Wnt target genes. They also participate in telomere maintenance by PARylating TRF1, which influences telomere length dynamics. Additional roles have been observed in vesicle trafficking and other signaling pathways, reflecting their broad interaction network.

In clinical research, tankyrases have been investigated as therapeutic targets in cancers with hyperactive Wnt signaling. Small-molecule inhibitors of tankyrase, such as XAV939 and G007-LK, stabilize AXIN and suppress Wnt signaling in preclinical models. Ongoing studies aim to define efficacious regimens and assess potential toxicities associated with tankyrase inhibition.

TNKS and TNKS2 are conserved vertebrate paralogs with overlapping and distinct contributions to cellular pathways, and their precise roles continue to be explored in normal physiology and disease contexts.