Abstract
Telomere length in humans is partly controlled by a feedback mechanism in which telomere elongation by telomerase is limited by the accumulation of the TRF1 complex at chromosome ends1,2,3,4,5. TRF1 itself can be inhibited by the poly(ADP-ribose) polymerase (PARP) activity of its interacting partner tankyrase 1, which abolishes its DNA binding activity in vitro and removes the TRF1 complex from telomeres in vivo. Here we report that the inhibition of TRF1 by tankyrase is in turn controlled by a second TRF1-interacting factor, TIN2 (ref. 6). Partial knockdown of TIN2 by small hairpin RNA in a telomerase-positive cell line resulted in telomere elongation, which is typical of reduced TRF1 function. Transient inhibition of TIN2 with small interfering RNA led to diminished telomeric TRF1 signals. This effect could be reversed with the PARP inhibitor 3-aminobenzamide and did not occur in cells overexpressing a PARP-dead mutant of tankyrase 1. TIN2 formed a ternary complex with TRF1 and tankyrase 1 and stabilized their interaction, an effect also observed with the PARP-dead mutant of tankyrase 1. In vitro, TIN2 protected TRF1 from poly(ADP-ribosyl)ation by tankyrase 1 without affecting tankyrase 1 automodification. These data identify TIN2 as a PARP modulator in the TRF1 complex and can explain how TIN2 contributes to the regulation of telomere length.
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References
Chong, L. et al. A human telomeric protein. Science 270, 1663–1667 (1995).
van Steensel, B. & de Lange, T. Control of telomere length by the human telomeric protein TRF1. Nature 385, 740–743 (1997).
Smogorzewska, A. et al. Control of human telomere length by TRF1 and TRF2. Mol. Cell. Biol. 20, 1659–1668 (2000).
Ancelin, K. et al. Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Mol. Cell. Biol. 22, 3474–3487 (2002).
Smogorzewska, A. & de Lange, T. Regulation of telomerase by telomeric proteins. Annu. Rev. Biochem. 73, 177–208 (2004).
Kim, S.H., Kaminker, P. & Campisi, J. TIN2, a new regulator of telomere length in human cells. Nat. Genet. 23, 405–412 (1999).
Hemann, M.T. et al. An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotype in vivo. Nat. Genet. 33, 396–400 (2003).
Karlseder, J. et al. Targeted deletion reveals an essential function for the telomere length regulator Trf1. Mol. Cell. Biol. 23, 6533–6541 (2003).
Iwano, T., Tachibana, M., Reth, M. & Shinkai, Y. Importance of TRF1 for Functional Telomere Structure. J. Biol. Chem. 279, 1442–1448 (2003).
Zhong, Z., Shiue, L., Kaplan, S. & de Lange, T. A mammalian factor that binds telomeric TTAGGG repeats in vitro. Mol. Cell. Biol. 12, 4834–4843 (1992).
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).
Smith, S., Giriat, I., Schmitt, A. & de Lange, T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 282, 1484–1487 (1998).
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).
De Rycker, M., Venkatesan, R.N., Wei, C. & Price, C.M. Vertebrate tankyrase domain structure and sterile alpha motif (SAM)-mediated multimerization. Biochem. J. 372, 87–96 (2003).
Lyon, R.J. et al. Identification of a novel human tankyrase through its interaction with the adaptor protein Grb14. J. Biol. Chem. 276, 17172–17180 (2001).
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).
Smith, S. & de Lange, T. Tankyrase promotes telomere elongation in human cells. Curr. Biol. 10, 1299–1302 (2000).
Chang, W., Dynek, J.N. & Smith, S. TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev. 17, 1328–1333 (2003).
Marsischky, G.T., Wilson, B.A. & Collier, R.J. Role of glutamic acid 988 of human poly-ADP-ribose polymerase in polymer formation. Evidence for active site similarities to the ADP-ribosylating toxins. J. Biol. Chem. 270, 3247–3254 (1995).
Loayza, D. & De Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 424, 1013–1018 (2003).
Acknowledgements
We thank J. Campisi and S. Kim for the human TIN2 cDNA and baculovirus, P. Cortes for advice on 293T transfection and sequential immunoprecipitations, G. Hannon for the retrovirus-based shRNA expression system, A. Himelblau and D. Hockemeyer for help in generating the antisera to TIN2 and K. Hoke and other members of T.d.L.'s laboratory for discussion and comments on this manuscript. This work was supported by grants from the US National Cancer Institute and Burroughs Welcome to T.d.L., by a Career Development Award from the US National Cancer Institute to J.Z.Y. and by a grant from the Translational & Integrative Medicine Research Fund from Sloan-Kettering Cancer Institute to J.Z.Y.
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Ye, JS., de Lange, T. TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet 36, 618–623 (2004). https://doi.org/10.1038/ng1360
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DOI: https://doi.org/10.1038/ng1360
