1. Biochemistry and Chemical Biology
  2. Cell Biology
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SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks

  1. Jaime Lopez-Mosqueda
  2. Karthik Maddi
  3. Stefan Prgomet
  4. Sissy Kalayil
  5. Ivana Marinovic-Terzic
  6. Janos Terzic
  7. Ivan Dikic  Is a corresponding author
  1. Goethe University School of Medicine, Germany
  2. University of Split, Croatia
Research Article
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Cite this article as: eLife 2016;5:e21491 doi: 10.7554/eLife.21491

Abstract

Ruijs-Aalfs syndrome is a segmental progeroid syndrome resulting from mutations in the SPRTN gene. Cells derived from patients with SPRTN mutations elicit genomic instability and persons afflicted with this syndrome developed hepatocellular carcinoma. Here we describe the molecular mechanism by which SPRTN contributes to genome stability and normal cellular homeostasis. We show that SPRTN is a DNA-dependent mammalian protease required for resolving cytotoxic DNA-protein crosslinks (DPCs); a function that had only been attributed to the metalloprotease Wss1 in budding yeast. We provide genetic evidence that SPRTN and Wss1 function distinctly in vivo to resolve DPCs. Upon DNA or ubiquitin binding, SPRTN can elicit proteolytic activity; cleaving DPC substrates or itself. SPRTN null cells or cells derived from patients with Ruijs-Aalfs syndrome are impaired in the resolution of covalent DPCs in vivo. Collectively, SPRTN is a mammalian protease required for resolving DNA-protein crosslinks in vivo whose function is compromised in Ruijs-Aalfs syndrome patients.

Article and author information

Author details

  1. Jaime Lopez-Mosqueda

    Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt am Main, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0301-1971
  2. Karthik Maddi

    Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt am Main, Germany
    Competing interests
    No competing interests declared.
  3. Stefan Prgomet

    Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt am Main, Germany
    Competing interests
    No competing interests declared.
  4. Sissy Kalayil

    Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt am Main, Germany
    Competing interests
    No competing interests declared.
  5. Ivana Marinovic-Terzic

    Department of Immunology and Medical Genetics, School of Medicine, University of Split, Split, Croatia
    Competing interests
    No competing interests declared.
  6. Janos Terzic

    Department of Immunology an Medical Genetics, School of Medicine, University of Split, Split, Croatia
    Competing interests
    No competing interests declared.
  7. Ivan Dikic

    Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt am Main, Germany
    For correspondence
    dikic@biochem2.uni-frankfurt.de
    Competing interests
    Ivan Dikic, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8156-9511

Funding

Deutsche Forschungsgemeinschaft (SFB1177)

  • Ivan Dikic

Deutsche Forschungsgemeinschaft (CEF-MC)

  • Ivan Dikic

Human Frontier Science Program (Postdoctoral fellowship)

  • Jaime Lopez-Mosqueda

LOEWE Zentrum CGT and Loewe Network Ub Net (Fellowships)

  • Ivan Dikic

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

Reviewing Editor

  1. Wade Harper, Harvard Medical School, United States

Publication history

  1. Received: September 14, 2016
  2. Accepted: November 15, 2016
  3. Accepted Manuscript published: November 17, 2016 (version 1)
  4. Version of Record published: November 29, 2016 (version 2)

Copyright

© 2016, Lopez-Mosqueda 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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