{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nADP‐ribosylation is a versatile post‐translational modification orchestrated by poly(ADP‐ribose) polymerases (PARPs) to regulate DNA repair, transcription, and diverse stress responses, with its reversal being critical for maintaining cellular homeostasis. In this context, OARD1—encoded by the C6orf130 gene and also known as MACROD1—has emerged as an important ADP‐ribosylhydrolase that interacts with PARPs to remove mono(ADP‐ribosyl) groups from protein substrates (notably on glutamate residues), thus contributing to the turnover and recycling of ADP‐ribosylation marks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "Dissecting its catalytic mechanism, structural and biochemical analyses have revealed that OARD1 possesses a canonical macrodomain fold featuring a deep ADP‐ribose binding cleft. Critical residues—including Ser‑35 and Asp‑125—are essential for its deacylase activity, which efficiently converts O‐acetyl‐, O‐propionyl‐, and O‐butyryl‐ADP‐ribose into ADP‐ribose and the corresponding small carboxylic acids. This deacylation not only reverses protein mono(ADP‐ribosyl)ation but also helps process the O‐acylated ADP‐ribose molecules produced during sirtuin‐mediated lysine deacylation, thereby linking metabolic by‐products with ADP‐ribose signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "At the cellular level, loss or mutation of OARD1 has been associated with defects in cell proliferation, DNA repair, and disruptions in organelle morphology. Studies report its pronounced mitochondrial presence in skeletal muscle and suggest, through analysis of its interactome, potential roles in RNA metabolism and the maintenance of nucleolar architecture. Positioning OARD1 among other ADP‐ribosylhydrolases—with recent findings demonstrating, for instance, the reversal of DNA‐linked ADP‐ribosylation by related enzymes—underscores the enzyme’s broader significance in the dynamic regulation of ADP‐ribosylation signaling pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Reza Sharifi, Rosa Morra, C Denise Appel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2013.51"}], "href": "https://doi.org/10.1038/emboj.2013.51"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23481255"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23481255"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Eva Barkauskaite, Gytis Jankevicius, Ivan Ahel "}, {"type": "b", "children": [{"type": "t", "text": "Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2015.05.007"}], "href": "https://doi.org/10.1016/j.molcel.2015.05.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26091342"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26091342"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Francis C Peterson, Dawei Chen, Betsy L Lytle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Orphan macrodomain protein (human C6orf130) is an O-acyl-ADP-ribose deacylase: solution structure and catalytic properties."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.276238"}], "href": "https://doi.org/10.1074/jbc.M111.276238"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21849506"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21849506"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "R Žaja, G Aydin, B E Lippok, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-020-64623-y"}], "href": "https://doi.org/10.1038/s41598-020-64623-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32427867"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32427867"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Callum Tromans-Coia, Andrea Sanchi, Giuliana K Moeller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TARG1 protects against toxic DNA ADP-ribosylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkab771"}], "href": "https://doi.org/10.1093/nar/gkab771"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34508355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34508355"}]}]}]}