title: Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease.
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.
authors.affiliation: Biomedical Sciences Division, Human Genetics Research Centre, St George's University of London, London, UK. rsharifi@sgul.ac.uk
authors.forename: Reza
authors.initials: R
authors.lastname: Sharifi
authors.forename: Rosa
authors.initials: R
authors.lastname: Morra
authors.forename: C Denise
authors.initials: CD
authors.lastname: Appel
authors.forename: Michael
authors.initials: M
authors.lastname: Tallis
authors.forename: Barry
authors.initials: B
authors.lastname: Chioza
authors.forename: Gytis
authors.initials: G
authors.lastname: Jankevicius
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Ivan
authors.initials: I
authors.lastname: Matic
authors.forename: Ege
authors.initials: E
authors.lastname: Ozkan
authors.forename: Barbara
authors.initials: B
authors.lastname: Golia
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schellenberg
authors.forename: Ria
authors.initials: R
authors.lastname: Weston
authors.forename: Jason G
authors.initials: JG
authors.lastname: Williams
authors.forename: Marianna N
authors.initials: MN
authors.lastname: Rossi
authors.forename: Hamid
authors.initials: H
authors.lastname: Galehdari
authors.forename: Juno
authors.initials: J
authors.lastname: Krahn
authors.forename: Alexander
authors.initials: A
authors.lastname: Wan
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
authors.forename: Dragana
authors.initials: D
authors.lastname: Ahel
authors.forename: Ron
authors.initials: R
authors.lastname: Hay
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Ladurner
authors.forename: Gyula
authors.initials: G
authors.lastname: Timinszky
authors.forename: R Scott
authors.initials: RS
authors.lastname: Williams
authors.forename: Ivan
authors.initials: I
authors.lastname: Ahel
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D006026:Glycoside Hydrolases / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics; D010375:Pedigree; D011064:Poly Adenosine Diphosphate Ribose / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013869:Thiolester Hydrolases / Q000235:genetics / Q000502:physiology*
chemical_list: D011064:Poly Adenosine Diphosphate Ribose; C581913:OARD1 protein, human; D013869:Thiolester Hydrolases; D006026:Glycoside Hydrolases