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Tankyrase-targeted therapeutics: expanding opportunities in the PARP family

Nature Reviews Drug Discovery volume 11, pages 923–936 (2012)Cite this article

Subjects

Key Points

  • The tankyrases TANK1 and TANK2 are members of the poly(ADP-ribose) polymerase (PARP) superfamily of enzymes that catalyse the transfer of many ADP-ribose moieties onto their protein substrates. They have roles in telomere maintenance, WNT signalling, mitosis and insulin-mediated glucose uptake.

  • Another member of the PARP superfamily, PARP1, is involved in DNA damage signalling and base excision repair. It has been the focus of many drug development efforts, particularly for the treatment of cancers with mutations in breast cancer susceptibility type 1 (BRCA1) or BRCA2, as simultaneous inhibition of the base excision and homologous repair pathways has a synthetic lethal effect on cancer cells; however, so far, no PARP1 inhibitors have been approved for clinical use.

  • The WNT pathway controls cellular proliferation and differentiation through the transcriptional activity of β-catenin, which is degraded by a complex including the tankyrase substrate axis inhibition protein (AXIN) when WNT signalling is not active. This pathway is dysregulated in many cancers, leading to constitutive β-catenin activity, but contains few 'druggable' targets.

  • The role of tankyrases in WNT signalling has driven the development of tankyrase-specific PARP inhibitors, which have now been shown to reduce β-catenin transcriptional activity in cancer cells and effectively kill cells with mutations in the β-catenin destruction complex component adenomatous polyposis coli (APC).

  • This exciting new class of PARP inhibitors could be useful in treating cancer as well as other conditions such as pulmonary fibrosis; however, lessons must be learned from the clinical development of PARP1 inhibitors. Careful preclinical work and clinical trial design is essential for the success of tankyrase inhibitors in the clinic.

Abstract

The poly(ADP-ribose) polymerase (PARP) protein superfamily has wide-ranging roles in cellular processes such as DNA repair and WNT signalling. Efforts to pharmacologically target PARP enzymes have largely focused on PARP1 and the closely related PARP2, but recent work highlighting the role of another family member, tankyrase 1 (TANK1; also known as PARP5A and ARTD5), in the control of WNT signalling has fuelled interest in the development of additional inhibitors to target this enzyme class. Tankyrase function is also implicated in other processes such as the regulation of telomere length, lung fibrogenesis and myelination, suggesting that tankyrase inhibitors could have broad clinical utility. Here, we discuss the biology of tankyrases and the discovery of tankyrase-specific inhibitors. We also consider the challenges that lie ahead for the clinical development of PARP family inhibitors in general.

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Figure 1: PARsylation by PARPs.
Figure 2: Tankyrase structure.
Figure 3: Tankyrase functions.

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References

  1. Durkacz, B. W., Omidiji, O., Gray, D. A. & Shall, S. (ADP-ribose)n participates in DNA excision repair. Nature 283, 593–596 (1980).

    Article  CAS  PubMed  Google Scholar 

  2. Durkacz, B. W., Shall, S. & Irwin, J. The effect of inhibition of (ADP-ribose)n biosynthesis on DNA repair assayed by the nucleoid technique. Eur. J. Biochem. 121, 65–69 (1981).

    Article  CAS  PubMed  Google Scholar 

  3. Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H. & Poirier, G. G. PARP inhibition: PARP1 and beyond. Nature Rev. Cancer 10, 293–301 (2010).

    Article  CAS  Google Scholar 

  4. Purnell, M. R. & Whish, W. J. Novel inhibitors of poly(ADP-ribose) synthetase. Biochem. J. 185, 775–777 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Durkacz, B. W., Irwin, J. & Shall, S. Inhibition of (ADP-ribose)n biosynthesis retards DNA repair but does not inhibit DNA repair synthesis. Biochem. Biophys. Res. Commun. 101, 1433–1441 (1981).

    Article  CAS  PubMed  Google Scholar 

  6. Wahlberg, E. et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nature Biotech. 30, 283–288 (2012). This study provides a systematic evaluation of inhibitors of the PARP family, allowing direct comparison of the specificity and potency of many known PARP inhibitors.

    Article  CAS  Google Scholar 

  7. Huang, S. M. et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614–620 (2009). This study characterizes the role of tankyrase in WNT signalling and identifies XAV939, the first tankyrase-specific PARP inhibitor.

    Article  CAS  PubMed  Google Scholar 

  8. Smith, S., Giriat, I., Schmitt, A. & de Lange, T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 282, 1484–1487 (1998). Tankyrase is first identified in this study as a PARP that functions at mammalian telomeres.

    Article  CAS  PubMed  Google Scholar 

  9. Hsiao, S. J. & Smith, S. Tankyrase function at telomeres, spindle poles, and beyond. Biochimie 90, 83–92 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Kaminker, P. G. et al. TANK2, a new TRF1-associated poly(ADP-ribose) polymerase, causes rapid induction of cell death upon overexpression. J. Biol. Chem. 276, 35891–35899 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Chiang, Y. J. et al. Tankyrase 1 and tankyrase 2 are essential but redundant for mouse embryonic development. PLoS ONE 3, e2639 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Guettler, S. et al. Structural basis and sequence rules for substrate recognition by tankyrase explain the basis for cherubism disease. Cell 147, 1340–1354 (2011). This study defines the consensus sequence for the recognition of tankyrase substrates and uses this finding to identify other potential tankyrase substrates — including 3BP2, which is shown to be involved in the disease known as cherubism.

    Article  CAS  PubMed  Google Scholar 

  13. 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. 24, 1944–1955 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Morrone, S., Cheng, Z., Moon, R. T., Cong, F. & Xu, W. Crystal structure of a tankyrase–axin complex and its implications for axin turnover and tankyrase substrate recruitment. Proc. Natl Acad. Sci. USA 109, 1500–1505 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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. 277, 14116–14126 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Chi, N. W. & Lodish, H. F. Tankyrase is a Golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles. J. Biol. Chem. 275, 38437–38444 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Yeh, T. Y., Sbodio, J. I. & Chi, N. W. Mitotic phosphorylation of tankyrase, a PARP that promotes spindle assembly, by GSK3. Biochem. Biophys. Res. Commun. 350, 574–579 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Ha, G. H. et al. Tankyrase-1 function at telomeres and during mitosis is regulated by Polo-like kinase-1-mediated phosphorylation. Cell Death Differ. 19, 321–332 (2012).

    Article  PubMed  CAS  Google Scholar 

  19. Yu, M. et al. PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation. Oncogene 24, 1982–1993 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Casas-Selves, M. et al. Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Cancer Res. 72, 4154–4164 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Buseman, C. M., Wright, W. E. & Shay, J. W. Is telomerase a viable target in cancer? Mutat. Res. 730, 90–97 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Smogorzewska, A. & de Lange, T. Regulation of telomerase by telomeric proteins. Annu. Rev. Biochem. 73, 177–208 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Palm, W. & de Lange, T. How shelterin protects mammalian telomeres. Annu. Rev. Genet. 42, 301–334 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Smith, S. & de Lange, T. Tankyrase promotes telomere elongation in human cells. Curr. Biol. 10, 1299–1302 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Lee, T. H., Perrem, K., Harper, J. W., Lu, K. P. & Zhou, X. Z. The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance. J. Biol. Chem. 281, 759–768 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Her, Y. R. & Chung, I. K. Ubiquitin ligase RLIM modulates telomere length homeostasis through a proteolysis of TRF1. J. Biol. Chem. 284, 8557–8566 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bailey, S. M. et al. The kinase activity of DNA-PK is required to protect mammalian telomeres. DNA Repair 3, 225–233 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Williams, E. S. et al. Telomere dysfunction and DNA-PKcs deficiency: characterization and consequence. Cancer Res. 69, 2100–2107 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dregalla, R. C. et al. Regulatory roles of tankyrase 1 at telomeres and in DNA repair: suppression of T-SCE and stabilization of DNA-PKcs. Aging 2, 691–708 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Donigian, J. R. & de Lange, T. The role of the poly(ADP-ribose) polymerase tankyrase1 in telomere length control by the TRF1 component of the shelterin complex. J. Biol. Chem. 282, 22662–22667 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Cook, B. D., Dynek, J. N., Chang, W., Shostak, G. & Smith, S. Role for the related poly(ADP-ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol. Cell. Biol. 22, 332–342 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Seimiya, H., Muramatsu, Y., Ohishi, T. & Tsuruo, T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell 7, 25–37 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Cerone, M. A., Burgess, D. J., Naceur-Lombardelli, C., Lord, C. J. & Ashworth, A. High-throughput RNAi screening reveals novel regulators of telomerase. Cancer Res. 71, 3328–3340 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Clevers, H. & Nusse, R. Wnt/β-catenin signaling and disease. Cell 149, 1192–1205 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. He, X. et al. A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science 275, 1652–1654 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Tamai, K. et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 407, 530–535 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Hart, M. J., de los Santos, R., Albert, I. N., Rubinfeld, B. & Polakis, P. Downregulation of β-catenin by human axin and its association with the APC tumor suppressor, β-catenin and GSK3β. Curr. Biol. 8, 573–581 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Li, V. S. et al. Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex. Cell 149, 1245–1256 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Morin, P. J. et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787–1790 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, Y. et al. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nature Cell Biol. 13, 623–629 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Callow, M. G. et al. Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt signaling. PLoS ONE 6, e22595 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhou, Z. D., Chan, C. H., Xiao, Z. C. & Tan, E. K. Ring finger protein 146/iduna is a poly(ADP-ribose) polymer binding and PARsylation dependent E3 ubiquitin ligase. Cell Adh. Migr. 5, 463–471 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kang, H. C. et al. Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage. Proc. Natl Acad. Sci. USA 108, 14103–14108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tenbaum, S. P. et al. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nature Med. 18, 892–901 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Wang, H., Hao, J. & Hong, C. C. Cardiac induction of embryonic stem cells by a small molecule inhibitor of Wnt/β-catenin signaling. ACS Chem. Biol. 6, 192–197 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Ulsamer, A. et al. Axin pathway activity regulates in vivo pY654–β-catenin accumulation and pulmonary fibrosis. J. Biol. Chem. 287, 5164–5172 (2012). This paper shows that tankyrase has a role in pulmonary fibrosis, and the authors use a small-molecule inhibitor to show that tankyrase inhibitors could have potential for the treatment of this condition.

    Article  CAS  PubMed  Google Scholar 

  50. Fancy, S. P. et al. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nature Neurosci. 14, 1009–1016 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Hsiao, S. J. & Smith, S. Sister telomeres rendered dysfunctional by persistent cohesion are fused by NHEJ. J. Cell Biol. 184, 515–526 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dynek, J. N. & Smith, S. Resolution of sister telomere association is required for progression through mitosis. Science 304, 97–100 (2004). This study defines the essential role of tankyrase in resolving cohesion of sister chromatids between replication and mitosis.

    Article  CAS  PubMed  Google Scholar 

  53. Chang, W., Dynek, J. N. & Smith, S. NuMA is a major acceptor of poly(ADP-ribosyl)ation by tankyrase 1 in mitosis. Biochem. J. 391, 177–184 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chang, P., Coughlin, M. & Mitchison, T. J. Tankyrase-1 polymerization of poly(ADP-ribose) is required for spindle structure and function. Nature Cell Biol. 7, 1133–1139 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Boehler, C. et al. Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. Proc. Natl Acad. Sci. USA 108, 2783–2788 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chou, H. Y., Chou, H. T. & Lee, S. C. CDK-dependent activation of poly(ADP-ribose) polymerase member 10 (PARP10). J. Biol. Chem. 281, 15201–15207 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Yeh, T. Y., Sbodio, J. I., Tsun, Z. Y., Luo, B. & Chi, N. W. Insulin-stimulated exocytosis of GLUT4 is enhanced by IRAP and its partner tankyrase. Biochem. J. 402, 279–290 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Guo, H. L. et al. The Axin/TNKS complex interacts with KIF3A and is required for insulin-stimulated GLUT4 translocation. Cell Res. 22, 1246–1257 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Levaot, N. et al. Loss of tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. Cell 147, 1324–1339 (2011). This study, in conjunction with that of reference 12, shows how mutations in 3BP2 prevent tankyrase-mediated PARsylation and degradation, and lead to cherubism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li, Z. et al. Herpes simplex virus requires poly(ADP-ribose) polymerase activity for efficient replication and induces extracellular signal-related kinase-dependent phosphorylation and ICP0-dependent nuclear localization of tankyrase 1. J. Virol. 86, 492–503 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. McCabe, N. et al. Targeting tankyrase 1 as a therapeutic strategy for BRCA-associated cancer. Oncogene 28, 1465–1470 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Daniels, M. J., Wang, Y., Lee, M. & Venkitaraman, A. R. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306, 876–879 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Chen, B. et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nature Chem. Biol. 5, 100–107 (2009).

    Article  CAS  Google Scholar 

  64. Waaler, J. et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res. 72, 2822–2832 (2012). This study provides proof-of-concept evidence that tankyrase inhibitors could be efficacious in the treatment of APC-mutated colorectal cancer.

    Article  CAS  PubMed  Google Scholar 

  65. Yashiroda, Y. et al. A novel yeast cell-based screen identifies flavone as a tankyrase inhibitor. Biochem. Biophys. Res. Commun. 394, 569–573 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Narwal, M., Venkannagari, H. & Lehtio, L. Structural basis of selective inhibition of human tankyrases. J. Med. Chem. 55, 1360–1367 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Gunaydin, H., Gu, Y. & Huang, X. Novel binding mode of a potent and selective tankyrase inhibitor. PLoS ONE 7, e33740 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Shultz, M. D. 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. 55, 1127–1136 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Kirby, C. A., Cheung, A., Fazal, A., Shultz, M. D. & Stams, T. Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 68, 115–118 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zaremba, T. & Curtin, N. J. PARP inhibitor development for systemic cancer targeting. Anticancer Agents Med. Chem. 7, 515–523 (2007).

    Article  CAS  Google Scholar 

  71. Muramatsu, Y., Ohishi, T., Sakamoto, M., Tsuruo, T. & Seimiya, H. Cross-species difference in telomeric function of tankyrase 1. Cancer Sci. 98, 850–857 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Lord, C. J. & Ashworth, A. Biology-driven cancer drug development: back to the future. BMC Biol. 8, 38 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Lievre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66, 3992–3995 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Kleine, H. et al. Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-ribosylation. Mol. Cell 32, 57–69 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Hottiger, M. O., Hassa, P. O., Luscher, B., Schuler, H. & Koch-Nolte, F. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem. Sci. 35, 208–219 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Manke, I. A., Lowery, D. M., Nguyen, A. & Yaffe, M. B. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302, 636–639 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Langelier, M. F., Planck, J. L., Roy, S. & Pascal, J. M. Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Science 336, 728–732 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Fisher, A. E., Hochegger, H., Takeda, S. & Caldecott, K. W. Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase. Mol. Cell. Biol. 27, 5597–5605 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Mortusewicz, O., Ame, J. C., Schreiber, V. & Leonhardt, H. Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells. Nucleic Acids Res. 35, 7665–7675 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rulten, S. L. et al. PARP-3 and APLF function together to accelerate nonhomologous end-joining. Mol. Cell 41, 33–45 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Kickhoefer, V. A. et al. The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase. J. Cell Biol. 146, 917–928 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lara, P. C., Pruschy, M., Zimmermann, M. & Henriquez-Hernandez, L. A. MVP and vaults: a role in the radiation response. Radiat. Oncol. 6, 148 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Welsby, I., Hutin, D. & Leo, O. Complex roles of members of the ADP-ribosyl transferase super family in immune defences: looking beyond PARP1. Biochem. Pharmacol. 84, 11–20 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Ogata, N., Ueda, K., Kawaichi, M. & Hayaishi, O. Poly(ADP-ribose) synthetase, a main acceptor of poly(ADP-ribose) in isolated nuclei. J. Biol. Chem. 256, 4135–4137 (1981).

    Article  CAS  PubMed  Google Scholar 

  85. Dantzer, F. et al. Involvement of poly(ADP-ribose) polymerase in base excision repair. Biochimie 81, 69–75 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. David, S. S., O'Shea, V. L. & Kundu, S. Base-excision repair of oxidative DNA damage. Nature 447, 941–950 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Delaney, C. A. et al. Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines. Clin. Cancer Res. 6, 2860–2867 (2000).

    CAS  PubMed  Google Scholar 

  88. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Chen, J. J., Silver, D., Cantor, S., Livingston, D. M. & Scully, R. BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway. Cancer Res. 59, 1752s–1756s (1999).

    CAS  PubMed  Google Scholar 

  91. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. De Vos, M., Schreiber, V. & Dantzer, F. The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochem. Pharmacol. 84, 137–146 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Brenner, J. C. et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19, 664–678 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Erener, S. et al. Inflammasome-activated caspase 7 cleaves PARP1 to enhance the expression of a subset of NF-κB target genes. Mol. Cell 46, 200–211 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Mendeleyev, J., Kirsten, E., Hakam, A., Buki, K. G. & Kun, E. Potential chemotherapeutic activity of 4-iodo-3-nitrobenzamide. Metabolic reduction to the 3-nitroso derivative and induction of cell death in tumor cells in culture. Biochem. Pharmacol. 50, 705–714 (1995).

    Article  CAS  PubMed  Google Scholar 

  96. Patel, A. G., De Lorenzo, S. B., Flatten, K. S., Poirier, G. G. & Kaufmann, S. H. Failure of iniparib to inhibit poly(ADP-ribose) polymerase in vitro. Clin. Cancer Res. 18, 1655–1662 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Davidovic, L., Vodenicharov, M., Affar, E. B. & Poirier, G. G. Importance of poly(ADP-ribose) glycohydrolase in the control of poly(ADP-ribose) metabolism. Exp. Cell Res. 268, 7–13 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Huang, H. Y. et al. Role of poly(ADP-ribose) glycohydrolase in the regulation of cell fate in response to benzo(a)pyrene. Exp. Cell Res. 318, 682–690 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Zhou, Y., Feng, X. & Koh, D. W. Activation of cell death mediated by apoptosis-inducing factor due to the absence of poly(ADP-ribose) glycohydrolase. Biochemistry 50, 2850–2859 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Mortusewicz, O., Fouquerel, E., Ame, J. C., Leonhardt, H. & Schreiber, V. PARG is recruited to DNA damage sites through poly(ADP-ribose)- and PCNA-dependent mechanisms. Nucleic Acids Res. 39, 5045–5056 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ame, J. C. et al. Radiation-induced mitotic catastrophe in PARG-deficient cells. J. Cell Sci. 122, 1990–2002 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Fathers, C., Drayton, R. M., Solovieva, S. & Bryant, H. E. Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells. Cell Cycle 11, 990–997 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Finch, K. E., Knezevic, C. E., Nottbohm, A. C., Partlow, K. C. & Hergenrother, P. J. Selective small molecule inhibition of poly(ADP-ribose) glycohydrolase (PARG). ACS Chem. Biol. 7, 563–570 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bisht, K. K. et al. GDP-mannose-4,6-dehydratase is a cytosolic partner of tankyrase 1 that inhibits its poly(ADP-ribose) polymerase activity. Mol. Cell. Biol. 32, 3044–3053 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Menear, K. A. et al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J. Med. Chem. 51, 6581–6591 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Jones, P. et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J. Med. Chem. 52, 7170–7185 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Miknyoczki, S. et al. The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. Mol. Cancer Ther. 6, 2290–2302 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Work in our laboratory is funded by the UK Wellcome Trust as part of the Seeding Drug Discovery Initiative, Breakthrough Breast Cancer, Cancer Research UK, American Association for Cancer Research, Breast Cancer Research Foundation, the Breast Cancer Campaign and Susan G. Komen for the Cure Foundation. We acknowledge National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Royal Marsden Hospital Biomedical Research Centre.

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Authors and Affiliations

  1. The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK

    Jenna L. Riffell, Christopher J. Lord & Alan Ashworth

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  1. Jenna L. Riffell
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  2. Christopher J. Lord
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  3. Alan Ashworth
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Correspondence to Christopher J. Lord or Alan Ashworth.

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Competing interests

C.J.L. and A.A. are inventors on patents describing the use of poly(ADP-ribose) polymerase (PARP) inhibitors and stand to gain under the ICR Rewards to Inventors Scheme.

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FURTHER INFORMATION

UK Institute of Cancer Research

Pfam database

Protein Data Bank

Glossary

iTRAQ

Isobaric tag for relative and absolute quantification; a proteomic technique that quantifies isotope-tagged proteins from different samples in one experiment.

Sister chromatid cohesion

The state in which two sister chromatids are bound together by the cohesin complex during mitosis, from prophase to metaphase.

Cherubism

A genetic disorder that results in bone, fibrous tissue and cyst formations along the jawline and lower part of the face. This disorder was originally termed cherubism owing to a perceived resemblance of sufferers to cherubs in Renaissance paintings.

Synthetic lethality

A relationship between the functions of two gene products; defined as a situation whereby a mutation or loss of function in either gene alone is compatible with viability, but defects in both genes lead to cell death.

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Riffell, J., Lord, C. & Ashworth, A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat Rev Drug Discov 11, 923–936 (2012). https://doi.org/10.1038/nrd3868

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