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A two-step mechanism for TRF2-mediated chromosome-end protection

Nature volume 494, pages 502–505 (2013)Cite this article

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Abstract

Mammalian telomeres repress DNA-damage activation at natural chromosome ends by recruiting specific inhibitors of the DNA-damage machinery that form a protective complex termed shelterin. Within this complex, TRF2 (also known as TERF2) has a crucial role in end protection through the suppression of ATM activation and the formation of end-to-end chromosome fusions1,2. Here we address the molecular properties of TRF2 that are both necessary and sufficient to protect chromosome ends in mouse embryonic fibroblasts. Our data support a two-step mechanism for TRF2-mediated end protection. First, the dimerization domain of TRF2 is required to inhibit ATM activation, the key initial step involved in the activation of a DNA-damage response (DDR). Next, TRF2 independently suppresses the propagation of DNA-damage signalling downstream of ATM activation. This novel modulation of the DDR at telomeres occurs at the level of the E3 ubiquitin ligase RNF168 (ref. 3). Inhibition of RNF168 at telomeres involves the deubiquitinating enzyme BRCC3 and the ubiquitin ligase UBR5, and is sufficient to suppress chromosome end-to-end fusions. This two-step mechanism for TRF2-mediated end protection helps to explain the apparent paradox of frequent localization of DDR proteins at functional telomeres without concurrent induction of detrimental DNA-repair activities.

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Figure 1: Critical role for the TRFH domain and the hinge domain of TRF2 in end protection.
Figure 2: Inhibition of RNF168 recruitment at chromosome ends.
Figure 3: The C-terminal portion of the hinge domain of TRF2 is necessary and sufficient to prevent 53BP1 localization at telomeres.
Figure 4: Mechanism of TRF2-mediated inhibition of RNF168.

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Acknowledgements

We thank T. de Lange, M. D. Weitzman, D. Durucher, X. Yu and X. Wu for providing reagents. We are grateful to A. Sfeir, T. Stracker, K. Miller and C. Attwooll for critical reading of the manuscript. This work was supported by a Pew Scholars Award (E.L.D.), the Novartis Advanced Discovery Institute (E.L.D.), National Institutes of Health AG038677 (E.L.D.), National Center for Research Resources (5P41RR011823-17) (J.R.Y.) and National Institute of General Medical Sciences (8 P41 GM103533-17) (J.R.Y.).

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Authors and Affiliations

  1. Department of Molecular and Experimental Medicine, Laboratory of Chromosome Biology and Genomic Stability, The Scripps Research Institute, La Jolla, 92037, California, USA

    Keiji Okamoto, Cristina Bartocci, Iliana Ouzounov & Eros Lazzerini Denchi

  2. Department of Chemical Physiology and Cell Biology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Jolene K. Diedrich & John R. Yates III

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  1. Keiji Okamoto
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  6. Eros Lazzerini Denchi
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Contributions

E.L.D. and K.O. conceived the experimental design. K.O., C.B., I.O. and E.L.D. performed the experiments and analysed the data. J.K.D. and J.R.Y. performed the mass spectrometry analysis. E.L.D. wrote the manuscript.

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Correspondence to Eros Lazzerini Denchi.

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Supplementary Information

This file contains Supplementary Figures 1-18, Supplementary Tables 1-2 and the legend for Supplementary Table 3 (see separate excel file). (PDF 11399 kb)

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Okamoto, K., Bartocci, C., Ouzounov, I. et al. A two-step mechanism for TRF2-mediated chromosome-end protection. Nature 494, 502–505 (2013). https://doi.org/10.1038/nature11873

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