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 & 5 others Ron Hay, Andreas G. Ladurner, Gyula Timinszky, R. Scott Williams, Ivan Ahel

    Research output: Contribution to journalArticle

    143 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1225-1237
    Number of pages13
    JournalEMBO Journal
    Volume32
    Issue number9
    DOIs
    Publication statusPublished - 2 May 2013

    Keywords

    • ADP-ribose
    • POLY(ADP-RIBOSE) PAR POLYMER
    • BINDING
    • REPAIR
    • MECHANISM
    • CHROMATIN
    • FEATURES
    • macrodomain
    • PARP
    • DNA damage
    • RIBOSYLATION
    • DNA
    • IDENTIFICATION
    • neurodegeneration
    • MAMMALIAN-CELLS

    Cite this

    Sharifi, R., Morra, R., Appel, C. D., Tallis, M., Chioza, B., Jankevicius, G., ... Ahel, I. (2013). Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease. EMBO Journal, 32(9), 1225-1237. https://doi.org/10.1038/emboj.2013.51
    Sharifi, Reza ; Morra, Rosa ; Appel, C. Denise ; Tallis, Michael ; Chioza, Barry ; Jankevicius, Gytis ; Simpson, Michael A. ; Matic, Ivan ; Ozkan, Ege ; Golia, Barbara ; Schellenberg, Matthew J. ; Weston, Ria ; Williams, Jason G. ; Rossi, Marianna N. ; Galehdari, Hamid ; Krahn, Juno ; Wan, Alexander ; Trembath, Richard C. ; Crosby, Andrew H. ; Ahel, Dragana ; Hay, Ron ; Ladurner, Andreas G. ; Timinszky, Gyula ; Williams, R. Scott ; Ahel, Ivan. / Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease. In: EMBO Journal. 2013 ; Vol. 32, No. 9. pp. 1225-1237.
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    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.",
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    author = "Reza Sharifi and Rosa Morra and Appel, {C. Denise} and Michael Tallis and Barry Chioza and Gytis Jankevicius and Simpson, {Michael A.} and Ivan Matic and Ege Ozkan and Barbara Golia and Schellenberg, {Matthew J.} and Ria Weston and Williams, {Jason G.} and Rossi, {Marianna N.} and Hamid Galehdari and Juno Krahn and Alexander Wan and Trembath, {Richard C.} and Crosby, {Andrew H.} and Dragana Ahel and Ron Hay and Ladurner, {Andreas G.} and Gyula Timinszky and Williams, {R. Scott} and Ivan Ahel",
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    Sharifi, R, Morra, R, Appel, CD, Tallis, M, Chioza, B, Jankevicius, G, Simpson, MA, Matic, I, Ozkan, E, Golia, B, Schellenberg, MJ, Weston, R, Williams, JG, Rossi, MN, Galehdari, H, Krahn, J, Wan, A, Trembath, RC, Crosby, AH, Ahel, D, Hay, R, Ladurner, AG, Timinszky, G, Williams, RS & Ahel, I 2013, 'Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease', EMBO Journal, vol. 32, no. 9, pp. 1225-1237. https://doi.org/10.1038/emboj.2013.51

    Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease. / Sharifi, Reza; Morra, Rosa; Appel, C. Denise; Tallis, Michael; Chioza, Barry; Jankevicius, Gytis; Simpson, Michael A.; Matic, Ivan; Ozkan, Ege; Golia, Barbara; Schellenberg, Matthew J.; Weston, Ria; Williams, Jason G.; Rossi, Marianna N.; Galehdari, Hamid; Krahn, Juno; Wan, Alexander; Trembath, Richard C.; Crosby, Andrew H.; Ahel, Dragana; Hay, Ron; Ladurner, Andreas G.; Timinszky, Gyula; Williams, R. Scott; Ahel, Ivan.

    In: EMBO Journal, Vol. 32, No. 9, 02.05.2013, p. 1225-1237.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease

    AU - Sharifi, Reza

    AU - Morra, Rosa

    AU - Appel, C. Denise

    AU - Tallis, Michael

    AU - Chioza, Barry

    AU - Jankevicius, Gytis

    AU - Simpson, Michael A.

    AU - Matic, Ivan

    AU - Ozkan, Ege

    AU - Golia, Barbara

    AU - Schellenberg, Matthew J.

    AU - Weston, Ria

    AU - Williams, Jason G.

    AU - Rossi, Marianna N.

    AU - Galehdari, Hamid

    AU - Krahn, Juno

    AU - Wan, Alexander

    AU - Trembath, Richard C.

    AU - Crosby, Andrew H.

    AU - Ahel, Dragana

    AU - Hay, Ron

    AU - Ladurner, Andreas G.

    AU - Timinszky, Gyula

    AU - Williams, R. Scott

    AU - Ahel, Ivan

    PY - 2013/5/2

    Y1 - 2013/5/2

    N2 - 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.

    AB - 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.

    KW - ADP-ribose

    KW - POLY(ADP-RIBOSE) PAR POLYMER

    KW - BINDING

    KW - REPAIR

    KW - MECHANISM

    KW - CHROMATIN

    KW - FEATURES

    KW - macrodomain

    KW - PARP

    KW - DNA damage

    KW - RIBOSYLATION

    KW - DNA

    KW - IDENTIFICATION

    KW - neurodegeneration

    KW - MAMMALIAN-CELLS

    U2 - 10.1038/emboj.2013.51

    DO - 10.1038/emboj.2013.51

    M3 - Article

    VL - 32

    SP - 1225

    EP - 1237

    JO - EMBO Journal

    JF - EMBO Journal

    SN - 0261-4189

    IS - 9

    ER -

    Sharifi R, Morra R, Appel CD, Tallis M, Chioza B, Jankevicius G et al. Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease. EMBO Journal. 2013 May 2;32(9):1225-1237. https://doi.org/10.1038/emboj.2013.51