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DNA damage signalling prevents deleterious telomere addition at DNA breaks

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Abstract

The response to DNA damage involves regulation of several essential processes to maximize the accuracy of DNA damage repair and cell survival1. Telomerase has the potential to interfere with repair by inappropriately adding telomeres to DNA breaks. It was unknown whether cells modulate telomerase in response to DNA damage to increase the accuracy of repair. Here, we report that telomerase action is regulated as a part of the cellular response to DNA double-strand breaks (DSBs). Using yeast, we show that the main ATR/Mec1 DNA damage signalling pathway regulates telomerase action at DSBs. After DNA damage, MEC1–RAD53–DUN1-dependent phosphorylation of the telomerase inhibitor Pif1 occurs. Using a separation of function PIF1 mutation, we show that this phosphorylation is specifically required for the Pif1-mediated telomerase inhibition that takes place at DNA breaks, but not for that at telomeres. Hence DNA damage signalling down-modulates telomerase action at DNA breaks through Pif1 phosphorylation, thus preventing aberrant healing of broken DNA ends by telomerase. These findings uncover a new regulatory mechanism that coordinates competing DNA end-processing activities and thereby promotes DNA repair accuracy and genome integrity.

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Figure 1: nPif1 is phosphorylated in response to DNA damage in a MEC1–RAD53-dependent manner.
Figure 2: pif1-4A is a separation of function phospho-site mutant, defective in telomerase inhibition specifically at DSBs and not telomeres.

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Acknowledgements

We thank members of the Blackburn and Harrington laboratories for encouraging discussions and useful ideas. We also thank C. Anderson for pEHB13045 and H. Interthal and N. E. Murray for critical reading of the manuscript and helpful suggestions. We thank the laboratory of L. A. Harrington for support of S.M. since February 2008 (with funds provided by the School of Biological Sciences, University of Edinburgh, and Wellcome Trust Programme Grant 84637 to L. A. Harrington). This work was supported by NIH grant GM26259 (to E.H.B.).

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of California, San Francisco, 94143, CA, USA

    Svetlana Makovets & Elizabeth H. Blackburn

  2. Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, EH9 3JR, UK

    Svetlana Makovets

Authors
  1. Svetlana Makovets
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  2. Elizabeth H. Blackburn
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Contributions

S.M. designed and performed the experiments and analysed the data. S.M. and E.H.B. discussed results and wrote the manuscript.

Corresponding author

Correspondence to Elizabeth H. Blackburn.

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The authors declare no competing financial interests.

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Makovets, S., Blackburn, E. DNA damage signalling prevents deleterious telomere addition at DNA breaks. Nat Cell Biol 11, 1383–1386 (2009). https://doi.org/10.1038/ncb1985

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