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Human Tankyrase 1 - catalytic PARP-domain

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PDB Code 2RF5 Target Class Poly ADP-ribose polymerase Target TNKS1 Alias PARP-5a, PARP5A, PARPL, TIN1, TINF1, TNKS, TNKS1 Disease Area/Function cancer Date Deposited Sep 28 2007 Authors LEHTIO, L., KARLBERG, T., ARROWSMITH, C., BERGLUND, H., BUSAM, R., COLLINS, R., DAHLGREN, L.G., EDWARDS, A., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., HERMAN, M.D., HOLMBERG-SCHIAVONE, L., JOHANSSON, I., KALLAS, A., KOTENYOVA, T., MOCHE, M., NORDLUND, P., NYMAN, T., PERSSON, C., SAGEMARK, J., SUNDSTROM, M., THORSELL, A.G., TRESAUGUES, L., VAN DEN BERG, S., WELIN, M., WEIGELT, J.

About this structure

Tankyrase (TRF1-interacting ankyrin related ADP-ribose polymerase) was first identified in 1998 (1) and found to interact with TRF1 – a component of the shelterin complex, which binds to, and protects, telomeric DNA. After its discovery, tankyrase has been shown to interact with various proteins linking it to telomere homeostasis and mitosis (2).

Tankyrase belongs to the 17 membered family of PARP-enzymes (3), that use NAD+ as a substrate to add poly-ADP-ribose to other proteins or themselves. Poly ADP-ribosylation is a covalent modification that often modulates the affinity of the target molecule towards its binding partners (3). PARP-1 is an established drug target for cancer and several PARP-1 inhibitors are currently in clinical trials (4). Tankyrases are modular proteins that, in addition to the catalytic PARP domain, also contain: HPS-, ANK-, and SAM-domains. The two human tankyrases, TNKS1 and 2 are very homologous in sequence, but TNKS2 lacks the N-terminal HSP-domain.

In telomere length control TNKS1 binds and poly-ADP ribosylates the shelterin component TRF1. This modification disrupts the shelterin complex and exposes telomeres to telomerase, facilitating elongation of the telomeric DNA. Telomerase activity is increased in several cancer cells and inhibition of telomerase activity provides an opportunity to develop new cancer therapies (5). Tankyrase inhibition has been demonstrated as an attractive mechanism to augment the effect of direct telomerase inhibition (6). The present structure of the catalytic PARP domain of TNKS1 will enable structure based design of specific TNKS1 inhibitors, in particular, and will add to the structural knowledge that provides a framework for development of selective PARP inhibitors in general (7).

References

  1. Smith, S., Giriat, I., Schmitt, A. and de Lange, T. (1998) Tankyrase, a poly(ADP ribose) polymerase at human telomeres. Science, 282, 1484-1487.
  2. Hsiao, S.J. and Smith, S. (2007) Tankyrase function at telomeres, spindle poles, and beyond. Biochimie. In press.
  3. Schreiber, V., Dantzer, F., Amé, J.C. and de Murcia, G. (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol., 7, 517-528.
  4. Ratnam, K. and Low, J.A. (2007) Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology. Clin. Cancer. Res., 13, 1383-1388.
  5. Zimmermann, S. and Martens, U.M. (2007) Telomeres and telomerase as targets for cancer therapy. Cell. Mol. Life Sci., 64, 906-921.
  6. Seimiya, H. (2006) The telomeric PARP, tankyrases, as targets for cancer therapy. Br. J. Cancer, 94, 341-345.
  7. Lehtiö L, Collins R, van den Berg S, Johansson A, Dahlgren L-G, Hammarström, M, Helleday T, Holmberg-Schiavone, L, Karlberg T and Weigelt J. Zinc Binding Catalytic Domain of Human Tankyrase 1. JMB 2008 May 23;379(1):136-45.