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Open Access

Deficiency of terminal ADP‐ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease

Reza Sharifi, Rosa Morra, C Denise Appel, Michael Tallis, Barry Chioza, Gytis Jankevicius, Michael A Simpson, Ivan Matic, Ege Ozkan, Barbara Golia, Matthew J Schellenberg, Ria Weston, Jason G Williams, Marianna N Rossi, Hamid Galehdari, Juno Krahn, Alexander Wan, Richard C Trembath, Andrew H Crosby, Dragana Ahel, Ron Hay, Andreas G Ladurner, Gyula Timinszky, R Scott Williams, Ivan Ahel

Author Affiliations

  1. Reza Sharifi (rsharifi{at}sgul.ac.uk)*,1,
  2. Rosa Morra2,
  3. C Denise Appel3,
  4. Michael Tallis2,
  5. Barry Chioza1,
  6. Gytis Jankevicius4,
  7. Michael A Simpson5,
  8. Ivan Matic6,
  9. Ege Ozkan1,
  10. Barbara Golia4,
  11. Matthew J Schellenberg3,
  12. Ria Weston2,
  13. Jason G Williams3,
  14. Marianna N Rossi2,
  15. Hamid Galehdari7,
  16. Juno Krahn3,
  17. Alexander Wan1,
  18. Richard C Trembath5,
  19. Andrew H Crosby1,
  20. Dragana Ahel2,
  21. Ron Hay6,
  22. Andreas G Ladurner (andreas.ladurner{at}med.lmu.de)*,4,8,9,
  23. Gyula Timinszky (gyula.timinszky{at}med.Imu.de)*,4,
  24. R Scott Williams (williamsrs{at}niehs.nih.gov)*,3 and
  25. Ivan Ahel (iahel{at}picr.man.ac.uk)*,2
  1. 1 Biomedical Sciences Division, Human Genetics Research Centre, St George's University of London, London, UK
  2. 2 Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK
  3. 3 Laboratory of Structural Biology, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
  4. 4 Faculty of Medicine, Butenandt Institute of Physiological Chemistry, Ludwig Maximilians University of Munich, Munich, Germany
  5. 5 Genetics and Molecular Medicine, King's College London, Guy's Hospital, London, UK
  6. 6 Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Scotland, UK
  7. 7 Genetics Department, Sciences Faculty, Ahvaz Shahid Chamran University, Ahvaz, Iran
  8. 8 Center for Integrated Protein Science Munich (CIPSM), Munich, Germany
  9. 9 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
  1. * Biomedical Sciences Division, Human Genetics Research Centre, St George's University of London, London SW17 0RE, UK. Tel.:+44 2087255361; Fax:+44 2087251039; E-mail: rsharifi{at}sgul.ac.uk

    Faculty of Medicine, Butenandt Institute of Physiological Chemistry, Ludwig Maximilians University of Munich, Butenandtstrasse 5, Munich 81377, Germany. Tel.:+49 89 2180 77095; Fax:+49 89 2180 77093; E-mail: andreas.ladurner{at}med.lmu.de

    Faculty of Medicine, Butenandt Institute of Physiological Chemistry, Ludwig Maximilians University of Munich, Butenandtstrasse 5, Munich 81377, Germany. Tel.:+49 89 2180 77100; Fax:+49 89 2180 77093; E-mail: gyula.timinszky{at}med.Imu.de

    Laboratory of Structural Biology, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. Tel.:+1 9195414652; E-mail: williamsrs{at}niehs.nih.gov

    Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. Tel.:+44 1619187375; Fax:+44 1614463109; E-mail: iahel{at}picr.man.ac.uk

  1. These authors contributed equally to this work.

Abstract

Adenosine diphosphate (ADP)‐ribosylation is a post‐translational protein modification implicated in the regulation of a range of cellular processes. A family of proteins that catalyse ADP‐ribosylation reactions are the poly(ADP‐ribose) (PAR) polymerases (PARPs). PARPs covalently attach an ADP‐ribose nucleotide to target proteins and some PARP family members can subsequently add additional ADP‐ribose units to generate a PAR chain. The hydrolysis of PAR chains is catalysed by PAR glycohydrolase (PARG). PARG is unable to cleave the mono(ADP‐ribose) unit directly linked to the protein and although the enzymatic activity that catalyses this reaction has been detected in mammalian cell extracts, the protein(s) responsible remain unknown. Here, we report the homozygous mutation of the c6orf130 gene in patients with severe neurodegeneration, and identify C6orf130 as a PARP‐interacting protein that removes mono(ADP‐ribosyl)ation on glutamate amino acid residues in PARP‐modified proteins. X‐ray structures and biochemical analysis of C6orf130 suggest a mechanism of catalytic reversal involving a transient C6orf130 lysyl‐(ADP‐ribose) intermediate. Furthermore, depletion of C6orf130 protein in cells leads to proliferation and DNA repair defects. Collectively, our data suggest that C6orf130 enzymatic activity has a role in the turnover and recycling of protein ADP‐ribosylation, and we have implicated the importance of this protein in supporting normal cellular function in humans.

  • Received January 22, 2013.
  • Accepted February 11, 2013.

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