{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADP‐ribosylation is a dynamic, reversible post‐translational modification in which poly(ADP‐ribose) polymerases (PARPs) transfer ADP‐ribose units from NAD⁺ onto target proteins, thereby modulating chromatin structure, transcription, DNA repair, cellular metabolism, and cell death. In response to DNA damage, PARP1 – the predominant nuclear ADP‐ribosyltransferase – rapidly detects strand breaks and catalyzes both mono‐ and poly(ADP‐ribosyl)ation, thereby orchestrating the recruitment and regulation of DNA repair factors and influencing repair pathway choice."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Recent studies have shown that modification by PARP1 frequently occurs on serine residues in a process that is stimulated by cofactors such as HPF1, with serine ADP‐ribosylation emerging as a predominant signal in the cellular response to DNA damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": " Equally important for maintaining homeostasis is the removal of ADP‐ribose modifications; enzymes such as ADP‐ribosylhydrolase 3 (ARH3) and poly(ADP‐ribose) glycohydrolase (PARG) counterbalance PARP activity by cleaving poly(ADP‐ribose) chains and, in the case of ARH3, specifically erasing serine‐linked ADP‐ribose marks. This de‐modification is critical not only for DNA repair but also for preventing inappropriate activation of cell death pathways such as parthanatos."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its well‐established roles in genome integrity, ADP‐ribosylation signaling modulates metabolic pathways—for example, by influencing hexokinase activity—and thereby couples nuclear events to cellular energy homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}, {"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Structural and functional studies have further delineated the active sites and regulatory motifs of both writers and erasers of ADP‐ribosylation, driving the development of selective inhibitors with promising applications in cancer therapy, neuroprotection, and beyond."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}, {"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": " Collectively, these findings underscore that the tightly regulated balance between ADP‐ribose addition by PARPs and its removal by hydrolases not only safeguards genomic integrity and transcriptional fidelity but also influences cell survival and stress responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "22"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Raga Krishnakumar, W Lee Kraus "}, {"type": "b", "children": [{"type": "t", "text": "The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2010.06.017"}], "href": "https://doi.org/10.1016/j.molcel.2010.06.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20603072"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20603072"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "John M Pascal "}, {"type": "b", "children": [{"type": "t", "text": "The comings and goings of PARP-1 in response to DNA damage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "DNA Repair (Amst) (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.dnarep.2018.08.022"}], "href": "https://doi.org/10.1016/j.dnarep.2018.08.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30177435"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30177435"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Attila Brunyanszki, Bartosz Szczesny, László Virág, et al. 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