TNKS1/PARP5A

TNKS1/PARP5A is a telomeric poly(ADP-ribose) polymerase that binds TRF1, a negative regulator of telomere length maintenance, through ankyrin repeats^[1]. Mechanistically, TNKS1 and TNKS2 regulate Wnt/β-catenin signaling because XAV939 stabilizes AXIN by inhibiting both tankyrase isoforms and promotes β-catenin degradation^[2]. In colorectal cancer models, optimized tankyrase inhibitors stabilize AXIN, reduce Wnt/β-catenin signaling, and suppress APC-mutant tumor growth^[3]. In human cells, tankyrase inhibition also induces telomeric DNA damage and telomere shortening, linking Wnt pathway modulation with telomere-maintenance readouts^[4]. Compared with TNKS2/PARP5B, TNKS1 shares telomere-length maintenance capacity, but both isoforms are required to resolve telomere cohesion and maintain mitotic spindle integrity^[5]. TNKS1 also shows isoform-focused relevance in TNF-induced death, where tankyrase-1 acts as a native complex 2 component and tankyrase inhibitors sensitize cells to death signaling^[6]. For experimental applications, TNKS1/TNKS2 inhibitors therefore support pathway-dissection studies involving AXIN stabilization, β-catenin signaling, APC-mutant colorectal cancer models, telomere biology, and TNF death-complex regulation^[2][3][4][6].