Summary: A group of telomere associated proteins that interact with TRF1 PROTEIN, contain ANKYRIN REPEATS and have poly(ADP-ribose) polymerase activity.

Top Publications

  1. Seimiya H. The telomeric PARP, tankyrases, as targets for cancer therapy. Br J Cancer. 2006;94:341-5 pubmed
    ..b>Tankyrases are poly(ADP-ribose) polymerases that enhance telomerase access to telomeres...
  2. Seimiya H, Smith S. The telomeric poly(ADP-ribose) polymerase, tankyrase 1, contains multiple binding sites for telomeric repeat binding factor 1 (TRF1) and a novel acceptor, 182-kDa tankyrase-binding protein (TAB182). J Biol Chem. 2002;277:14116-26 pubmed
    ..We discuss potential roles for tankyrase 1-mediated higher order complexes at telomeres and at other subcellular sites. ..
  3. Lehtiö L, Collins R, van den Berg S, Johansson A, Dahlgren L, Hammarström M, et al. Zinc binding catalytic domain of human tankyrase 1. J Mol Biol. 2008;379:136-45 pubmed publisher
    b>Tankyrases are recently discovered proteins implicated in many important functions in the cell including telomere homeostasis and mitosis...
  4. Yeh T, Beiswenger K, Li P, Bolin K, Lee R, Tsao T, et al. Hypermetabolism, hyperphagia, and reduced adiposity in tankyrase-deficient mice. Diabetes. 2009;58:2476-85 pubmed publisher
    ..Its chromosomal locus 8p23.1 is linked to monogenic forms of diabetes in certain kindred. We hypothesize that TNKS is involved in energy homeostasis in mammals...
  5. James R, Davidson K, Bosch K, Biechele T, Robin N, Taylor R, et al. WIKI4, a novel inhibitor of tankyrase and Wnt/ß-catenin signaling. PLoS ONE. 2012;7:e50457 pubmed publisher
    ..While TNKS has previously been shown to be the target of small molecule inhibitors of Wnt/ß-catenin signaling, WIKI4 is structurally distinct from previously identified TNKS inhibitors. ..
  6. Distler A, Deloch L, Huang J, Dees C, Lin N, Palumbo Zerr K, et al. Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling. Ann Rheum Dis. 2013;72:1575-80 pubmed publisher
    ..Here, we investigated tankyrases as novel molecular targets for inhibition of canonical Wnt signalling in fibrotic diseases...
  7. Sbodio J, Chi N. Identification of a tankyrase-binding motif shared by IRAP, TAB182, and human TRF1 but not mouse TRF1. NuMA contains this RXXPDG motif and is a novel tankyrase partner. J Biol Chem. 2002;277:31887-92 pubmed
    ..Herein we describe a novel RXXPDG motif shared by IRAP, TAB182, and human TRF1 that mediates their binding to tankyrases. Interestingly, mouse TRF1 lacks this motif and thus does not bind either tankyrase-1 or -2...
  8. Bisht K, Dudognon C, Chang W, Sokol E, Ramirez A, Smith S. GDP-mannose-4,6-dehydratase is a cytosolic partner of tankyrase 1 that inhibits its poly(ADP-ribose) polymerase activity. Mol Cell Biol. 2012;32:3044-53 pubmed publisher
    ..We speculate that association of tankyrase 1 with GMD in the cytosol sequesters tankyrase 1 in an inactive stable form that can be tapped by other target proteins as needed. ..
  9. Narwal M, Venkannagari H, Lehtiö L. Structural basis of selective inhibition of human tankyrases. J Med Chem. 2012;55:1360-7 pubmed publisher
    b>Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions...

More Information


  1. Chang W, Dynek J, Smith S. NuMA is a major acceptor of poly(ADP-ribosyl)ation by tankyrase 1 in mitosis. Biochem J. 2005;391:177-84 pubmed
    ..We discuss our result in terms of a model where PARsylation of NuMA by tankyrase 1 in mitosis could play a role in sister telomere separation and/or mitotic progression. ..
  2. Casás Selves M, Kim J, Zhang Z, Helfrich B, Gao D, Porter C, et al. Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Cancer Res. 2012;72:4154-64 pubmed publisher
    ..Targeting the Wnt-tankyrase-?-catenin pathway together with EGFR inhibition may improve clinical outcome in patients with NSCLC. ..
  3. Ozaki Y, Matsui H, Asou H, Nagamachi A, Aki D, Honda H, et al. Poly-ADP ribosylation of Miki by tankyrase-1 promotes centrosome maturation. Mol Cell. 2012;47:694-706 pubmed publisher
    ..Our data suggest that PARsylation of Miki by tankyrase-1 is a key initial event promoting prometaphase. ..
  4. De Rycker M, Venkatesan R, Wei C, Price C. Vertebrate tankyrase domain structure and sterile alpha motif (SAM)-mediated multimerization. Biochem J. 2003;372:87-96 pubmed
    b>Tankyrases 1 and 2 are two highly related poly(ADP-ribose) polymerases that interact with a variety of cytoplasmic and nuclear proteins...
  5. Bae J, Donigian J, Hsueh A. Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of apoptosis. J Biol Chem. 2003;278:5195-204 pubmed
    ..Thus, interaction of Mcl-1L and Mcl-1S with tankyrase 1 could serve as a unique mechanism to decrease the expression of these Bcl-2 family proteins, thereby leading to the modulation of the apoptosis pathway. ..
  6. Seimiya H, Muramatsu Y, Smith S, Tsuruo T. Functional subdomain in the ankyrin domain of tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomere elongation. Mol Cell Biol. 2004;24:1944-55 pubmed
    ..This work provides evidence that specific ARC-TRF1 interactions play roles in the essential catalytic function of tankyrase 1. ..
  7. Chang P, Coughlin M, Mitchison T. Tankyrase-1 polymerization of poly(ADP-ribose) is required for spindle structure and function. Nat Cell Biol. 2005;7:1133-9 pubmed
    ..We also demonstrate a requirement for tankyrase-1 in the assembly of bipolar spindles, and identify the spindle-pole protein NuMA as a substrate for covalent modification by tankyrase-1. ..
  8. Levaot N, Voytyuk O, Dimitriou I, Sircoulomb F, Chandrakumar A, Deckert M, et al. Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. Cell. 2011;147:1324-39 pubmed publisher
    ..Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the SRC, SYK, and VAV signaling pathways...
  9. Fearon E. PARsing the phrase "all in for Axin"- Wnt pathway targets in cancer. Cancer Cell. 2009;16:366-8 pubmed publisher
  10. Lehtiö L, Chi N, Krauss S. Tankyrases as drug targets. FEBS J. 2013;280:3576-93 pubmed publisher
    ..b>Tankyrases are implicated in a multitude of cellular functions, including telomere homeostasis, mitotic spindle formation, ..
  11. Chiang Y, Hsiao S, Yver D, Cushman S, Tessarollo L, Smith S, et al. Tankyrase 1 and tankyrase 2 are essential but redundant for mouse embryonic development. PLoS ONE. 2008;3:e2639 pubmed publisher
    b>Tankyrases are proteins with poly(ADP-ribose) polymerase activity...
  12. Larsson E, Jansson A, Ng F, Then S, Panicker R, Liu B, et al. Fragment-based ligand design of novel potent inhibitors of tankyrases. J Med Chem. 2013;56:4497-508 pubmed publisher
    b>Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases...
  13. Shultz M, Majumdar D, CHIN D, Fortin P, Feng Y, Gould T, et al. Structure-efficiency relationship of [1,2,4]triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrases. J Med Chem. 2013;56:7049-59 pubmed publisher
    b>Tankyrases 1 and 2 are members of the poly(ADP-ribose) polymerase (PARP) family of enzymes that modulate Wnt pathway signaling...
  14. Narwal M, Fallarero A, Vuorela P, Lehtiö L. Homogeneous screening assay for human tankyrase. J Biomol Screen. 2012;17:593-604 pubmed publisher
    ..The assay is robust and will be useful for screening new tankyrase inhibitors. ..
  15. Bao R, Christova T, Song S, Angers S, Yan X, Attisano L. Inhibition of tankyrases induces Axin stabilization and blocks Wnt signalling in breast cancer cells. PLoS ONE. 2012;7:e48670 pubmed publisher
    ..The levels of Axin are in turn controlled by tankyrases, members of the PARP-family of poly-ADP-ribosylation enzymes...
  16. Guettler S, LaRose J, Petsalaki E, Gish G, Scotter A, Pawson T, et al. Structural basis and sequence rules for substrate recognition by Tankyrase explain the basis for cherubism disease. Cell. 2011;147:1340-54 pubmed publisher
    ..Dysregulation of substrate recognition by Tankyrases underlies the human disease cherubism...
  17. Karlberg T, Markova N, Johansson I, Hammarström M, Schütz P, Weigelt J, et al. Structural basis for the interaction between tankyrase-2 and a potent Wnt-signaling inhibitor. J Med Chem. 2010;53:5352-5 pubmed publisher
    We report two crystal structures of the PARP domain of human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling...
  18. Dynek J, Smith S. Resolution of sister telomere association is required for progression through mitosis. Science. 2004;304:97-100 pubmed
    ..Thus, telomeres may require a unique tankyrase 1-dependent mechanism for sister chromatid resolution before anaphase. ..
  19. Scherthan H, Jerratsch M, Li B, Smith S, Hulten M, Lock T, et al. Mammalian meiotic telomeres: protein composition and redistribution in relation to nuclear pores. Mol Biol Cell. 2000;11:4189-203 pubmed
    ..The latter form during preleptotene/leptotene and are present during entire prophase I. ..
  20. Gelmini S, Poggesi M, Distante V, Bianchi S, Simi L, Luconi M, et al. Tankyrase, a positive regulator of telomere elongation, is over expressed in human breast cancer. Cancer Lett. 2004;216:81-7 pubmed
    ..No relationship was found between tankyrase and hTERT mRNA expression in breast cancers. According to our results, tankyrase expression appeared up regulated in breast cancers. ..
  21. Yeh T, Sbodio J, Tsun Z, Luo B, Chi N. Insulin-stimulated exocytosis of GLUT4 is enhanced by IRAP and its partner tankyrase. Biochem J. 2007;402:279-90 pubmed
    ..Collectively, these findings suggest that physiological GSV trafficking depends in part on the presence of IRAP in these vesicles, and that this process is regulated by tankyrase and probably its PARP activity. ..
  22. Hsiao S, Poitras M, Cook B, Liu Y, Smith S. Tankyrase 2 poly(ADP-ribose) polymerase domain-deleted mice exhibit growth defects but have normal telomere length and capping. Mol Cell Biol. 2006;26:2044-54 pubmed
    ..Together, these results suggest that Tnks2 has a role in normal growth and development but is not essential for telomere length maintenance or telomere capping in mice. ..
  23. Callow M, Tran H, Phu L, Lau T, Lee J, Sandoval W, et al. Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt signaling. PLoS ONE. 2011;6:e22595 pubmed publisher
    ..RNF146 also destabilizes tankyrases TNKS1 and TNKS2 proteins and, in a reciprocal relationship, tankyrase activity reduces RNF146 protein levels...
  24. Cook B, Dynek J, Chang W, Shostak G, Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol. 2002;22:332-42 pubmed
    ..These findings establish tankyrase 2 as a bona fide PARP, with itself and TRF1 as acceptors of ADP-ribosylation, and suggest the possibility of a role for tankyrase 2 at telomeres. ..
  25. Gunaydin H, Gu Y, Huang X. Novel binding mode of a potent and selective tankyrase inhibitor. PLoS ONE. 2012;7:e33740 pubmed publisher
    b>Tankyrases (TNKS1 and TNKS2) are key regulators of cellular processes such as telomere pathway and Wnt signaling. IWRs (inhibitors of Wnt response) have recently been identified as potent and selective inhibitors of tankyrases...
  26. Seimiya H, Muramatsu Y, Ohishi T, Tsuruo T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell. 2005;7:25-37 pubmed
    ..This study implies that both enzyme activity and accessibility to telomeres can be targets for telomerase inhibition. ..
  27. Shultz M, Kirby C, Stams T, CHIN D, Blank J, Charlat O, et al. [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: antagonists of the Wnt pathway that inhibit tankyrases 1 and 2 via novel adenosine pocket binding. J Med Chem. 2012;55:1127-36 pubmed publisher
    ..Furthermore, a cocrystal structure of compound 24 complexed to TNKS1 demonstrates an alternate binding mode for PARP family member proteins that does not involve interactions with the nicotinamide binding pocket. ..
  28. Riffell J, Lord C, Ashworth A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat Rev Drug Discov. 2012;11:923-36 pubmed publisher
    ..Here, we discuss the biology of tankyrases and the discovery of tankyrase-specific inhibitors...
  29. Liu C, He X. Destruction of a destructor: a new avenue for cancer therapeutics targeting the Wnt pathway. J Mol Cell Biol. 2010;2:70-3 pubmed publisher
    ..This inhibitor targets an unsuspected cellular enzyme, Tankyrase, which controls the destruction of a beta-catenin destructor. ..
  30. Narwal M, Haikarainen T, Fallarero A, Vuorela P, Lehtiö L. Screening and structural analysis of flavones inhibiting tankyrases. J Med Chem. 2013;56:3507-17 pubmed publisher
    ..Flavone has been previously identified as a tankyrase inhibitor, and to further elucidate whether tankyrases would be inhibited by other flavonoids, we performed a systematic screening of tankyrase 2 inhibitory activity ..
  31. McCabe N, Cerone M, Ohishi T, Seimiya H, Lord C, Ashworth A. Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer. Oncogene. 2009;28:1465-70 pubmed publisher
    ..We propose that inhibition of Tankyrase 1 could be therapeutically exploited in BRCA-associated cancers. ..
  32. Bisht K, Daniloski Z, Smith S. SA1 binds directly to DNA through its unique AT-hook to promote sister chromatid cohesion at telomeres. J Cell Sci. 2013;126:3493-503 pubmed publisher
    ..We suggest that a specialized cohesion mechanism may be required to accommodate the high level of DNA replication-associated repair at telomeres. ..
  33. Bregman H, Gunaydin H, Gu Y, Schneider S, Wilson C, DiMauro E, et al. Discovery of a class of novel tankyrase inhibitors that bind to both the nicotinamide pocket and the induced pocket. J Med Chem. 2013;56:1341-5 pubmed publisher
    Potent and selective inhibitors of tankyrases have recently been characterized to bind to an induced pocket...
  34. Yeh T, Meyer T, Schwesinger C, Tsun Z, Lee R, Chi N. Tankyrase recruitment to the lateral membrane in polarized epithelial cells: regulation by cell-cell contact and protein poly(ADP-ribosyl)ation. Biochem J. 2006;399:415-25 pubmed
  35. Karner C, Merkel C, Dodge M, Ma Z, Lu J, Chen C, et al. Tankyrase is necessary for canonical Wnt signaling during kidney development. Dev Dyn. 2010;239:2014-23 pubmed publisher
    ..However, the absence of any activity during zebrafish embryogenesis suggested that the tankyrases may not be general/core components of the Wnt pathway...
  36. Wahlberg E, Karlberg T, Kouznetsova E, Markova N, Macchiarulo A, Thorsell A, et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol. 2012;30:283-8 pubmed publisher
    ..for the ability to bind to the catalytic domains of 13 of the 17 human PARP family members including the tankyrases, TNKS1 and TNKS2...
  37. Lau T, Chan E, Callow M, Waaler J, Boggs J, Blake R, et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res. 2013;73:3132-44 pubmed publisher
    ..These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic. ..
  38. Busch A, Johnson K, Stan R, Sanglikar A, Ahmed Y, Dmitrovsky E, et al. Evidence for tankyrases as antineoplastic targets in lung cancer. BMC Cancer. 2013;13:211 pubmed publisher
    ..Taken together, these findings implicate the use of TNKS inhibitors to target the Wnt pathway to combat lung cancer. ..
  39. Smith S, Giriat I, Schmitt A, de Lange T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science. 1998;282:1484-7 pubmed
    ..ADP-ribosylation of TRF1 diminished its ability to bind to telomeric DNA in vitro, suggesting that telomere function in human cells is regulated by poly(ADP-ribosyl)ation. ..
  40. Smith S, de Lange T. Tankyrase promotes telomere elongation in human cells. Curr Biol. 2000;10:1299-302 pubmed
    ..Our results indicate that tankyrase can induce telomere elongation in human cells. We propose that tankyrase-mediated ADP-ribosylation of TRF1 opens the telomeric complex, allowing access to telomerase. ..
  41. Smith S, de Lange T. Cell cycle dependent localization of the telomeric PARP, tankyrase, to nuclear pore complexes and centrosomes. J Cell Sci. 1999;112 ( Pt 21):3649-56 pubmed
    ..Indeed, localization of exogenously-expressed tankyrase to telomeres was dependent upon co-transfection with TRF1. These data indicate that the subcellular localization of tankyrase can be regulated by both the cell cycle and TRF1. ..
  42. Ye J, de Lange T. TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet. 2004;36:618-23 pubmed
    ..These data identify TIN2 as a PARP modulator in the TRF1 complex and can explain how TIN2 contributes to the regulation of telomere length. ..
  43. Kim M, Dudognon C, Smith S. Tankyrase 1 regulates centrosome function by controlling CPAP stability. EMBO Rep. 2012;13:724-32 pubmed publisher
    ..Hence, tankyrase 1-mediated PARsylation regulates CPAP levels during the cell cycle to limit centriole elongation and ensure normal centrosome function...
  44. Huang S, Mishina Y, Liu S, Cheung A, Stegmeier F, Michaud G, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009;461:614-20 pubmed publisher
    ..Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies. ..
  45. Hsiao S, Smith S. Sister telomeres rendered dysfunctional by persistent cohesion are fused by NHEJ. J Cell Biol. 2009;184:515-26 pubmed publisher
    ..These results demonstrate that the timely removal of sister telomere cohesion is essential for the formation of a protective structure at chromosome ends after DNA replication in S/G2 phase of the cell cycle. ..
  46. Cockman M, Webb J, Kramer H, Kessler B, Ratcliffe P. Proteomics-based identification of novel factor inhibiting hypoxia-inducible factor (FIH) substrates indicates widespread asparaginyl hydroxylation of ankyrin repeat domain-containing proteins. Mol Cell Proteomics. 2009;8:535-46 pubmed publisher
    ..These findings indicate that asparaginyl hydroxylation is likely to be widespread among the approximately 300 ARD-containing species in the human proteome. ..
  47. Yeh T, Sbodio J, Nguyen M, Meyer T, Lee R, Chi N. Tankyrase-1 overexpression reduces genotoxin-induced cell death by inhibiting PARP1. Mol Cell Biochem. 2005;276:183-92 pubmed
    ..Our findings therefore indicate a cytoprotective function of tankyrase-1 mediated through altered NAD(+) homeostasis and inhibition of PARP 1 function. ..
  48. Dregalla R, Zhou J, Idate R, Battaglia C, Liber H, Bailey S. Regulatory roles of tankyrase 1 at telomeres and in DNA repair: suppression of T-SCE and stabilization of DNA-PKcs. Aging (Albany NY). 2010;2:691-708 pubmed
    ..We provide the first evidence for regulation of DNA-PKcs by tankyrase 1 PARP activity and taken together, identify roles of tankyrase 1 with implications not only for DNA repair and telomere biology, but also for cancer and aging. ..
  49. Hsiao S, Smith S. Tankyrase function at telomeres, spindle poles, and beyond. Biochimie. 2008;90:83-92 pubmed
    ..This review summarizes our current knowledge of tankyrases focusing on their localization, binding partners, and function.
  50. Chi N, Lodish H. Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles. J Biol Chem. 2000;275:38437-44 pubmed
    ..We speculate that tankyrase may be involved in the long term effect of the MAPK cascade on the metabolism of GLUT4 vesicles. ..
  51. Canudas S, Houghtaling B, Kim J, Dynek J, Chang W, Smith S. Protein requirements for sister telomere association in human cells. EMBO J. 2007;26:4867-78 pubmed
    ..Our studies indicate that sister telomere association in human cells is mediated by a novel association between a cohesin subunit and components of telomeric chromatin. ..
  52. Shebzukhov Y, Lavrik I, Karbach J, Khlgatian S, Koroleva E, Belousov P, et al. Human tankyrases are aberrantly expressed in colon tumors and contain multiple epitopes that induce humoral and cellular immune responses in cancer patients. Cancer Immunol Immunother. 2008;57:871-81 pubmed
    b>Tankyrases 1 and 2 are telomere-associated poly(ADP-ribose) polymerases (PARP) that can positively regulate telomere elongation and interact with multiple cellular proteins...
  53. Chiang Y, Nguyen M, Gurunathan S, Kaminker P, Tessarollo L, Campisi J, et al. Generation and characterization of telomere length maintenance in tankyrase 2-deficient mice. Mol Cell Biol. 2006;26:2037-43 pubmed
    ..This finding suggests that either mouse tankyrases 1 and 2 have redundant functions in telomere length maintenance or that mouse tankyrase 2 differs from human ..