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Multiple roles for MRE11 at uncapped telomeres

Nature volume 460, pages 914–918 (2009)Cite this article

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Abstract

Progressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response as a result of a cell’s inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks1. Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia and Rad3-related (ATR) kinase-dependent DNA damage response pathways, and promotes efficient non-homologous end-joining (NHEJ) of dysfunctional telomeres2,3,4,5. The mammalian MRE11–RAD50–NBS1 (MRN; NBS1 is also known as NBN) complex interacts with ATM to sense chromosomal double-strand breaks and coordinate global DNA damage responses6,7. Although the MRN complex accumulates at dysfunctional telomeres, it is not known whether mammalian MRN promotes repair at these sites. Here we address this question by using mouse alleles that either inactivate the entire MRN complex or eliminate only the nuclease activities of MRE11 (ref. 8). We show that cells lacking MRN do not activate ATM when telomeric repeat binding factor 2 (TRF2) is removed from telomeres, and ligase 4 (LIG4)-dependent chromosome end-to-end fusions are markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Notably, although cells deficient for MRE11 nuclease activity efficiently activate ATM and recruit 53BP1 (also known as TP53BP1) to deprotected telomeres, the 3′ telomeric overhang persists to prevent NHEJ-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3′ overhang in the setting of MRE11 nuclease deficiency restores LIG4-dependent chromosome fusions. Our data indicate a critical role for the MRN complex in sensing dysfunctional telomeres, and show that in the absence of TRF2, MRE11 nuclease activity removes the 3′ telomeric overhang to promote chromosome fusions. MRE11 can also protect newly replicated leading strand telomeres from NHEJ by promoting 5′ strand resection to generate POT1a–TPP1-bound 3′ overhangs.

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Figure 1: Activation of ATM but not ATR after TRF2 depletion requires the MRN complex but not MRE11 nuclease activity.
Figure 2: Requirement for MRN and MRE11 nuclease activity in NHEJ of telomeres lacking TRF2.
Figure 3: POT1a–TPP1 complex protects single-stranded overhangs from DNA repair.
Figure 4: LIG4 is required for repair of unprotected single-stranded telomeric overhangs.

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Change history

  • 13 August 2009

    Figure 3c was corrected on 13 August 2009.

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Acknowledgements

We are grateful to M. Zhao, Z. Lu, P. Iyengar and J. Buis for technical help. Both J. Karlseder and P. Carpenter are thanked for providing antibodies. S.C. acknowledges financial support from the National Institute on Aging (NIA) (RO1 AG028888), the National Cancer Institute (NCI) (RO1 CA129037), the Welch Foundation, the Susan G. Koman Race for the Cure Foundation, the Abraham and Phyllis Katz Foundation and the Michael Kadoorie Cancer Genetic Research Program. Y.D. was supported by an NCI Howard Temin Award (K01CA124461).

Author Contributions Y.D. designed and guided all experiments, helped write the paper and generated figures. X.G. performed all the experiments presented. D.O.F. provided MRE11 mouse cell lines for this study and assisted in the interpretation of results. S.C. conceived this study, analysed and interpreted the data, wrote the paper and finalized the figures.

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Author notes

  1. Yibin Deng & Xiaolan Guo

    Present address: Present address: Section of Cancer Genetics, The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.,

  2. Yibin Deng and Xiaolan Guo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Box 1010,

    Yibin Deng, Xiaolan Guo & Sandy Chang

  2. Department of Hematopathology, The M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,

    Sandy Chang

  3. Institute of Rheumatology and Immunology North Sichuan Medical College, Nanchong, Sichuan 637000, China ,

    Xiaolan Guo

  4. Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,

    David O. Ferguson

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  1. Yibin Deng
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  4. Sandy Chang
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Corresponding author

Correspondence to Sandy Chang.

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Deng, Y., Guo, X., Ferguson, D. et al. Multiple roles for MRE11 at uncapped telomeres. Nature 460, 914–918 (2009). https://doi.org/10.1038/nature08196

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