1. Chromosomes and Gene Expression
  2. Structural Biology and Molecular Biophysics
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CtIP forms a tetrameric dumbbell-shaped particle which bridges complex DNA end structures for double-strand break repair

  1. Oliver J Wilkinson
  2. Alejandro Martín-González
  3. Haejoo Kang
  4. Sarah J Northall
  5. Dale B Wigley
  6. Fernando Moreno-Herrero
  7. Mark Simon Dillingham  Is a corresponding author
  1. University of Bristol, United Kingdom
  2. Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cientificas, Spain
  3. Imperial College London, United Kingdom
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Cite this article as: eLife 2019;8:e42129 doi: 10.7554/eLife.42129

Abstract

CtIP is involved in the resection of broken DNA during the S and G2 phases of the cell cycle for repair by recombination. Acting with the MRN complex, it plays a particularly important role in handling complex DNA end structures by localised nucleolytic processing of DNA termini in preparation for longer range resection. Here we show that human CtIP is a tetrameric protein adopting a dumbbell architecture in which DNA binding domains are connected by long coiled-coils. The protein complex binds two short DNA duplexes with high affinity and bridges DNA molecules in trans. DNA binding is potentiated by dephosphorylation and is not specific for DNA end structures per se. However, the affinity for linear DNA molecules is increased if the DNA terminates with complex structures including forked ssDNA overhangs and nucleoprotein conjugates. This work provides a biochemical and structural basis for the function of CtIP at complex DNA breaks.

Article and author information

Author details

  1. Oliver J Wilkinson

    School of Biochemistry, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Alejandro Martín-González

    Department of Macromolecular Structures, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cientificas, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Haejoo Kang

    Section of Structural Biology, Department of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Sarah J Northall

    School of Biochemistry, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Dale B Wigley

    Section of Structural Biology, Department of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0786-6726
  6. Fernando Moreno-Herrero

    Department of Macromolecular Structures, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cientificas, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4083-1709
  7. Mark Simon Dillingham

    School of Biochemistry, University of Bristol, Bristol, United Kingdom
    For correspondence
    mark.dillingham@bristol.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4612-7141

Funding

Wellcome (100401/Z/12/Z)

  • Oliver J Wilkinson
  • Sarah J Northall
  • Mark Simon Dillingham

Cancer Research UK (C6913/A21608)

  • Haejoo Kang
  • Dale B Wigley

Spanish Ministry of Science (BFU2017-83794-P)

  • Fernando Moreno-Herrero

European Research Council (681299)

  • Fernando Moreno-Herrero

Spanish MINECO (BES-2015-071244)

  • Alejandro Martín-González

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Maria Spies, University of Iowa, United States

Publication history

  1. Received: September 19, 2018
  2. Accepted: January 1, 2019
  3. Accepted Manuscript published: January 2, 2019 (version 1)

Copyright

© 2019, Wilkinson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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