TANK2, a new TRF1-associated poly(ADP-ribose) polymerase, causes rapid induction of cell death upon overexpression

Tankyrase (TANK1) is a human telomere-associated poly(ADP-ribose) polymeras e (PARP) that binds the telomere-binding protein TRF1 and increases telomer e length when overexpressed. Here we report characterization of a second hu man tankyrase, tankyrase 2 (TANK2), which can also interact with TRF1 but h as properties distinct from those of TANK1. TANK2 is encoded by a 66-kiloba se pair gene (TNKS2) containing 28 exons, which express a 6.7-kilobase pair mRNA and a 1166-amino acid protein. The protein shares 85% amino acid iden tity with TANK1 in the ankyrin repeat, sterile a-motif, and PARP catalytic domains but has a unique N-terminal domain, which is conserved in the murin e TNKS2 gene. TANK2 interacted with TRF1 in yeast and in vitro and localize d predominantly to a perinuclear region, similar to the properties of TANK1 . In contrast to TANK1, however, TANK2 caused rapid cell death when highly overexpressed. TANK2-induced death featured loss of mitochondrial membrane potential, but not PARP1 cleavage, suggesting that TANK2 kills cells by nec rosis. The cell death was prevented by the PARP inhibitor 3-aminobenzamide. lit vivo, TANK2 may differ from TANK1 in its intrinsic or regulated PARP a ctivity or its substrate specificity.