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Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance

Nature Cell Biology volume 11, pages 97–105 (2009)Cite this article

Abstract

Telomeres are essential for maintaining cellular proliferative capacity and their loss has been implicated in ageing. A key regulator in telomere maintenance is the telomeric protein TRF1, which was also identified as Pin2 in a screen for Pin1. Pin1 is a unique prolyl isomerase that regulates protein conformation and function after phosphorylation. However, little is known about the role of Pin1 in telomere regulation or the modulation of TRF1 by upstream signals. Here we identify TRF1 as a major conserved substrate for Pin1 during telomere maintenance and ageing. Pin1 inhibition renders TRF1 resistant to protein degradation, enhances TRF1 binding to telomeres, and leads to gradual telomere loss in human cells and in mice. Pin1-deficient mice also show widespread premature ageing phenotypes within just one generation, similar to those in telomerase-deficient mice after 4–5 consecutive generations. Thus, Pin1 is an essential regulator of TRF1 stability, telomere maintenance and ageing.

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Figure 1: Pin1 binds to the pThr149–Pro motif in TRF1 in a phosphorylation-dependent and mitosis-specific manner.
Figure 2: Pin1 inhibition using three approaches renders TRF1 resistant to degradation, and the Pin1 action depends on its ability to act on the pThr149-Pro motif in TRF1.
Figure 3: Pin1 inhibition increases binding of TRF1 on telomeres and also leads to gradual and progressive telomere shortening in human cells.
Figure 4: Pin1 regulates telomere maintenance by acting through the TRF1-dependent mechanism.
Figure 5: Pin1 knockout results in elevated TRF1 levels, induces accelerated telomere loss and leads to a wide range of premature ageing phenotypes in mice.

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Acknowledgements

We are grateful to J. Frangioni and R. Bronson for assistance in determining bone-related and ageing phenotypes in Pin1 knockout mice, and W. Hahn for TERT and TER expression vectors. J. L. is a Human Frontiers Science Program Fellow, C.Y.S. is a Predoctoral Fellow of the DOD Breast Cancer Research Program and L. P. is a recipient of a Mentored Research Scientist Development Award from the NIH (K01). The work was supported by NIH grants to X. Z. Z. (R01CA122434) and K.P.L. (R01GM058556 and AG017870).

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  1. Department of Medicine, Cancer Biology Program and Biology of Aging Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, 02215, MA, USA

    Tae Ho Lee, Adrian Tun-Kyi, Rong Shi, Jormay Lim, Christina Soohoo, Greg Finn, Martin Balastik, Lucia Pastorino, Gerburg Wulf, Xiao Zhen Zhou & Kun Ping Lu

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Lee, T., Tun-Kyi, A., Shi, R. et al. Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance. Nat Cell Biol 11, 97–105 (2009). https://doi.org/10.1038/ncb1818

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