1. Biochemistry and Chemical Biology

Serine ADP-ribosylation reversal by the hydrolase ARH3

  1. Pietro Fontana
  2. Juan José Bonfiglio
  3. Luca Palazzo
  4. Edward Bartlett
  5. Ivan Matic  Is a corresponding author
  6. Ivan Ahel  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. Max Planck Institute for Biology of Ageing, Germany
https://doi.org/10.7554/eLife.28533
Share this article
Cite this article
  1. Pietro Fontana
  2. Juan José Bonfiglio
  3. Luca Palazzo
  4. Edward Bartlett
  5. Ivan Matic
  6. Ivan Ahel
(2017)
Serine ADP-ribosylation reversal by the hydrolase ARH3
eLife 6:e28533.
https://doi.org/10.7554/eLife.28533
  2. Download BibTeX
  3. Download .RIS

Abstract

ADP-ribosylation (ADPr) is a posttranslational modification (PTM) of proteins that controls many cellular processes, including DNA repair, transcription, chromatin regulation and mitosis. A number of proteins catalyse the transfer and hydrolysis of ADPr, and also specify how and when the modification is conjugated to the targets. We recently discovered a new form of ADPr that is attached to serine residues in target proteins (Ser-ADPr) and showed that this PTM is specifically made by PARP1/HPF1 and PARP2/HPF1 complexes. In this work, we found by quantitative proteomics that histone Ser-ADPr is reversible in cells during response to DNA damage. By screening for the hydrolase that is responsible for the reversal of Ser-ADPr, we identified ARH3/ADPRHL2 as capable of efficiently and specifically removing Ser-ADPr of histones and other proteins. We further showed that Ser-ADPr is a major PTM in cells after DNA damage and that this signalling is dependent on ARH3.

Article and author information

Author details

  1. Pietro Fontana

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Juan José Bonfiglio

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7767-0799

  3. Luca Palazzo

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5556-5549

  4. Edward Bartlett

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Ivan Matic

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    For correspondence
    imatic@age.mpg.de
    Competing interests
    The authors declare that no competing interests exist.

  6. Ivan Ahel

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    For correspondence
    ivan.ahel@path.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9446-3756

Funding

Wellcome (101794)

  • Ivan Ahel

Cancer Research UK (C35050/A22284)

  • Ivan Ahel

Deutsche Forschungsgemeinschaft (EXC 229)

  • Ivan Matic

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

Copyright

© 2017, Fontana 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.

Metrics

  • 4,460
    views
  • 893
    downloads
  • 208
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Citations by DOI

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Pietro Fontana
  2. Juan José Bonfiglio
  3. Luca Palazzo
  4. Edward Bartlett
  5. Ivan Matic
  6. Ivan Ahel
(2017)
Serine ADP-ribosylation reversal by the hydrolase ARH3
eLife 6:e28533.
https://doi.org/10.7554/eLife.28533

Share this article

https://doi.org/10.7554/eLife.28533

Categories and tags

Research organism

Further reading

    1. Biochemistry and Chemical Biology

    Serine is the major residue for ADP-ribosylation upon DNA damage

    Luca Palazzo, Orsolya Leidecker ... Ivan Ahel
    Research Advance Updated

    Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that synthesise ADP-ribosylation (ADPr), a reversible modification of proteins that regulates many different cellular processes. Several mammalian PARPs are known to regulate the DNA damage response, but it is not clear which amino acids in proteins are the primary ADPr targets. Previously, we reported that ARH3 reverses the newly discovered type of ADPr (ADPr on serine residues; Ser-ADPr) and developed tools to analyse this modification (Fontana et al., 2017). Here, we show that Ser-ADPr represents the major fraction of ADPr synthesised after DNA damage in mammalian cells and that globally Ser-ADPr is dependent on HPF1, PARP1 and ARH3. In the absence of HPF1, glutamate/aspartate becomes the main target residues for ADPr. Furthermore, we describe a method for site-specific validation of serine ADP-ribosylated substrates in cells. Our study establishes serine as the primary form of ADPr in DNA damage signalling.

    1. Biochemistry and Chemical Biology

    Post-translational Modifications: Reversing ADP-ribosylation

    Giuliana Katharina Moeller, Gyula Timinszky
    Insight

    The modification of serines by molecules of ADP-ribose plays an important role in signaling that the DNA in a cell has been damaged and needs to be repaired.