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Telomeres avoid end detection by severing the checkpoint signal transduction pathway


Telomeres protect the normal ends of chromosomes from being recognized as deleterious DNA double-strand breaks. Recent studies have uncovered an apparent paradox: although DNA repair is prevented, several proteins involved in DNA damage processing and checkpoint responses are recruited to telomeres in every cell cycle and are required for end protection1. It is currently not understood how telomeres prevent DNA damage responses from causing permanent cell cycle arrest. Here we show that fission yeast (Schizosaccharomyces pombe) cells lacking Taz1, an orthologue of human TRF1 and TRF2 (ref. 2), recruit DNA repair proteins (Rad22RAD52 and Rhp51RAD51, where the superscript indicates the human orthologue) and checkpoint sensors (RPA, Rad9, Rad26ATRIP and Cut5/Rad4TOPBP1) to telomeres. Despite this, telomeres fail to accumulate the checkpoint mediator Crb253BP1 and, consequently, do not activate Chk1-dependent cell cycle arrest. Artificially recruiting Crb253BP1 to taz1Δ telomeres results in a full checkpoint response and cell cycle arrest. Stable association of Crb253BP1 to DNA double-strand breaks requires two independent histone modifications: H4 dimethylation at lysine 20 (H4K20me2) and H2A carboxy-terminal phosphorylation (γH2A)3,4,5. Whereas γH2A can be readily detected, telomeres lack H4K20me2, in contrast to internal chromosome locations. Blocking checkpoint signal transduction at telomeres requires Pot1 and Ccq1, and loss of either Pot1 or Ccq1 from telomeres leads to Crb253BP1 foci formation, Chk1 activation and cell cycle arrest. Thus, telomeres constitute a chromatin-privileged region of the chromosomes that lack essential epigenetic markers for DNA damage response amplification and cell cycle arrest. Because the protein kinases ATM and ATR must associate with telomeres in each S phase to recruit telomerase6, exclusion of Crb253BP1 has a critical role in preventing telomeres from triggering cell cycle arrest.

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Figure 1: taz1 Δ telomeres undergo the DNA damage response without eliciting a checkpoint-dependent cell cycle arrest.
Figure 2: taz1 Δ telomeres initiate a DNA damage checkpoint response.
Figure 3: Dysfunctional taz1 Δ telomeres avert cell cycle arrest by preventing recruitment of Crb253BP1.
Figure 4: Pot1 and Ccq1 prevent Crb2 53BP1 -dependent checkpoints at telomeres.


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We thank J. Cooper, K. Tomita and the rest of the Telomere Biology Laboratory (Cancer Research UK, London) for support at the start of this project. We thank J. Cooper, T. Wolkow, P. Russell and A. M. Carr for strains and plasmids. We thank W. Kaufman for her initial effort in the establishment of HO strains. We are grateful to S. Grewal for sharing unpublished results and to D. Lydall for insights on the quantitative analysis of checkpoint activation. We thank K. Labib, L. Jansen, K. Xavier, R. Martinho and S. Lopes for critically reading the manuscript. T.C. and C.C.R. are supported by Fundação para a Ciência e a Tecnologia (FCT) postdoctoral fellowships. T.M.N. was supported by the Sidney Kimmel Scholar Program and his laboratory is supported by NIH grant GM078253. This work was supported by the FCT (PTDC/BIA-BCM/67261/2006) and the Association for International Cancer Research (06-396).

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T.C. helped with the design and executed most experiments. L.K. performed ChIP experiments. C.C.R. performed western and Southern blotting experiments. V.B. performed live cell analysis. B.A.M. established the ChIP and HO assays. T.M.N. contributed to the design of the ChIP and HO assays. All authors contributed with strains and data analysis. M.G.F. conceived the study, performed live cell analysis and wrote the paper.

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Correspondence to Miguel Godinho Ferreira.

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The authors declare no competing financial interests.

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Carneiro, T., Khair, L., Reis, C. et al. Telomeres avoid end detection by severing the checkpoint signal transduction pathway. Nature 467, 228–232 (2010).

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