1. Cell Biology
  2. Structural Biology and Molecular Biophysics

Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint

  1. Nicolas Bigot
  2. Matthew Day
  3. Robert A Baldock
  4. Felicity Z Watts
  5. Antony W Oliver  Is a corresponding author
  6. Laurence H Pearl  Is a corresponding author
  1. University of Sussex, United Kingdom
https://doi.org/10.7554/eLife.44353
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  1. Nicolas Bigot
  2. Matthew Day
  3. Robert A Baldock
  4. Felicity Z Watts
  5. Antony W Oliver
  6. Laurence H Pearl
(2019)
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
eLife 8:e44353.
https://doi.org/10.7554/eLife.44353
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Abstract

Coordination of the cellular response to DNA damage is organised by multi-domain 'scaffold' proteins, including 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation and ubiquitylation on other proteins, and are themselves carriers of such regulatory signals. Here we show that the DNA damage checkpoint regulating S-phase entry is controlled by a phosphorylation-dependent interaction of 53BP1 and TOPBP1. BRCT domains of TOPBP1 selectively bind conserved phosphorylation sites in the N-terminus of 53BP1. Mutation of these sites does not affect formation of 53BP1 or ATM foci following DNA damage, but abolishes recruitment of TOPBP1, ATR and CHK1 to 53BP1 damage foci, abrogating cell cycle arrest and permitting progression into S-phase. TOPBP1 interaction with 53BP1 is structurally complimentary to its interaction with RAD9-RAD1-HUS1, allowing these damage recognition factors to bind simultaneously to the same TOPBP1 molecule and cooperate in ATR activation in the G1 DNA damage checkpoint.

Data availability

Atomic Coordinates and structure factors have been deposited in the Protein Databank under accession codes: 6RML and 6RMM.

The following data sets were generated

Article and author information

Author details

  1. Nicolas Bigot

    Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4247-0217

  2. Matthew Day

    Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7218-867X

  3. Robert A Baldock

    Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4649-2966

  4. Felicity Z Watts

    Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Antony W Oliver

    Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
    For correspondence
    antony.oliver@sussex.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2912-8273

  6. Laurence H Pearl

    Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
    For correspondence
    Laurence.Pearl@sussex.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6910-1809

Funding

Cancer Research UK (C302/A14532)

  • Antony W Oliver
  • Laurence H Pearl

Cancer Research UK (C302/A24386)

  • Antony W Oliver
  • Laurence H Pearl

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

Reviewing Editor

  1. Volker Dötsch, Goethe University, Germany

Version history

  1. Received: December 12, 2018
  2. Accepted: May 25, 2019
  3. Accepted Manuscript published: May 28, 2019 (version 1)
  4. Version of Record published: June 12, 2019 (version 2)

Copyright

© 2019, Bigot 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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  1. Nicolas Bigot
  2. Matthew Day
  3. Robert A Baldock
  4. Felicity Z Watts
  5. Antony W Oliver
  6. Laurence H Pearl
(2019)
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
eLife 8:e44353.
https://doi.org/10.7554/eLife.44353

Share this article

https://doi.org/10.7554/eLife.44353

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