Abstract
Tankyrase (TANK1) is a human telomere-associated poly(ADP-ribose) polymerase (PARP) that binds the telomere-binding protein TRF1 and increases telomere length when overexpressed. Here we report characterization of a second human tankyrase, tankyrase 2 (TANK2), which can also interact with TRF1 but has properties distinct from those of TANK1. TANK2 is encoded by a 66-kilobase 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 identity with TANK1 in the ankyrin repeat, sterile alpha-motif, and PARP catalytic domains but has a unique N-terminal domain, which is conserved in the murine TNKS2 gene. TANK2 interacted with TRF1 in yeast and in vitro and localized 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 necrosis. The cell death was prevented by the PARP inhibitor 3-aminobenzamide. In vivo, TANK2 may differ from TANK1 in its intrinsic or regulated PARP activity or its substrate specificity.
Highlights
From the ‡Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 and §Geron Corporation, Menlo Park, California 94025
The protein shares 85% amino acid identity with TANK1 in the ankyrin repeat, sterile ␣-motif, and poly(ADP-ribose) polymerase (PARP) catalytic domains but has a unique N-terminal domain, which is conserved in the murine TNKS2 gene
Because telomeres are DNA ends that are anchored to the nuclear matrix [19, 22], and appear to elicit a DNA damage response when dysfunctional, PARPs are thought to participate in telomere maintenance and/or transmitting signals generated by dysfunctional telomeres
Summary
Vol 276, No 38, Issue of September 21, pp. 35891–35899, 2001 Printed in U.S.A. TANK2, a New TRF1-associated Poly(ADP-ribose) Polymerase, Causes Rapid Induction of Cell Death upon Overexpression*. The recent discovery of a telomere-associated poly(ADPribose) polymerase (PARP) [12] provides a potential mechanism by which telomeres transmit signals to cellular proteins that regulate the senescence and apoptotic responses. Because telomeres are DNA ends that are anchored to the nuclear matrix [19, 22], and appear to elicit a DNA damage response when dysfunctional, PARPs are thought to participate in telomere maintenance and/or transmitting signals generated by dysfunctional telomeres Consistent with this view, cells from knockout mice that lack PARP1, a classic PARP encoded by the ADPRT1 gene, have somewhat shorter (30%) telomeres than wild-type cells [15]. TANK1 (encoded by the TNKS gene on human chromosome 8) [12, 24] is a non-classic PARP that interacts with and ADPribosylates the telomere-binding protein TRF1 [12].
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