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MRE11–RAD50–NBS1 and ATM function as co-mediators of TRF1 in telomere length control

Nature Structural & Molecular Biology volume 14, pages 832–840 (2007)Cite this article

Abstract

Human telomeres are associated with ATM and the protein complex consisting of MRE11, RAD50 and NBS1 (MRN), which are central to maintaining genomic stability. Here we show that when targeted to telomeres, wild-type RAD50 downregulates telomeric association of TRF1, a negative regulator of telomere maintenance. TRF1 binding to telomeres is upregulated in cells deficient in NBS1 or under ATM inhibition. The TRF1 association with telomeres induced by ATM inhibition is abrogated in cells lacking MRE11 or NBS1, suggesting that MRN and ATM function in the same pathway controlling TRF1 binding to telomeres. The ability of TRF1 to interact with telomeric DNA in vitro is impaired by ATM-mediated phosphorylation. We propose that MRN is required for TRF1 phosphorylation by ATM and that such phosphorylation results in the release of TRF1 from telomeres, promoting telomerase access to the ends of telomeres.

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Figure 1: Fusion proteins interact with endogenous MRE11 at telomeres.
Figure 2: The wild-type fusion protein promotes telomere elongation by downregulating TRF1 association with telomeric DNA.
Figure 3: Loss of NBS1 promotes TRF1 binding to telomeres.
Figure 4: ATM inhibition upregulates TRF1 binding to telomeres, leading to telomere shortening.
Figure 5: Control of TRF1 binding to telomeres by ATM requires MRE11 and NBS1.
Figure 6: Phosphorylation by ATM impairs TRF1 interaction with telomeric DNA.
Figure 7: Analysis of the role of SQ sites in TRF1 binding to telomeric DNA.
Figure 8: Model for MRN- and ATM-mediated control of TRF1 in modulating telomerase-dependent telomere synthesis.

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Acknowledgements

We thank T. de Lange (Rockefeller University) for providing crucial reagents, including wild-type RAP1, plasmids pLPC-Myc-RAD50, pcDNA3-Myc-TRF1 and pTH12, antibodies to RAD50, MRE11, NBS1, RAP1, TRF2 and TRF1, cell lines AT22IJE-T and NBS-ILB1 stably expressing pBabe-puro or pBabe-puro-NBS1, and baculovirus-derived recombinant TRF1. We also thank J. Petrini (Sloan-Kettering Institute) for wild-type RAD50 complementary DNA and the cell line ATLD2, and J.R. Walker and members of the Zhu laboratory for critical comments. X.-D.Z. is a Canadian Institutes of Health Research New Investigator, and this work was supported by grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.

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  1. Department of Biology, LSB438 McMaster University, 1280 Main St. West, Hamilton, L8S4K1, Ontario, Canada

    Yili Wu, Shujie Xiao & Xu-Dong Zhu

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  1. Yili Wu
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Y.W. and S.X. performed the experiments. X.-D.Z. conceived and analyzed the experiments and wrote the paper.

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Correspondence to Xu-Dong Zhu.

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Wu, Y., Xiao, S. & Zhu, XD. MRE11–RAD50–NBS1 and ATM function as co-mediators of TRF1 in telomere length control. Nat Struct Mol Biol 14, 832–840 (2007). https://doi.org/10.1038/nsmb1286

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