{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPIDD1 is a p53‐inducible death domain protein that functions as a molecular switch in response to DNA damage. It plays a critical role in triggering apoptosis by assembling into the so‐called “PIDDosome,” a complex that facilitates caspase‐2 activation via interaction with the adaptor RAIDD. In parallel, PIDD1 also directs NF‑κB signaling through complexes involving RIP1 and NEMO, thereby promoting cell survival under genotoxic stress. Its activity is tightly regulated by autoproteolytic processing, which generates distinct fragments that determine whether the cell initiates programmed cell death or activates pro‐survival pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlternative splicing and post‐translational modifications further diversify PIDD1 function. Several isoforms exist that differ in their ability to interact with partner proteins; for example, distinct splicing variants can either promote caspase‐2 activation or counteract apoptotic signals. In addition, nuclear relocalization events—such as the translocation of the death domain–containing fragment to the nucleolus via interaction with nucleolin—highlight how spatial control of PIDD1 participates in fine‐tuning the balance between cell death and survival. Moreover, phosphorylation of its death domain (for instance, by ATM) acts as a binary switch that favors recruitment of RAIDD over RIP1, thus decisively steering the downstream apoptotic cascade."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in apoptosis, PIDD1 exerts multiple non‐canonical functions that integrate cell cycle regulation, DNA repair, and stress responses. It contributes to DNA maintenance processes such as non-homologous end joining and translesion synthesis, and it has been implicated in modulating chemoresistance through sequestration of KEAP1, thereby stabilizing NRF2. In addition, recent studies have linked PIDD1 to centrosome surveillance and the activation of inflammatory signaling via NF‑κB, underscoring its role in coupling DNA damage checkpoints to innate immune responses. Interactions with chaperones like Hsp90 and regulatory kinases including ATR further elaborate a complex network by which PIDD1 coordinates cell fate decisions, and pathogenic mutations in PIDD1’s death domain have been associated with neurodevelopmental disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "17"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_fs", "start_ref": "18", "end_ref": "24"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Antoine Tinel, Jürg Tschopp "}, {"type": "b", "children": [{"type": "t", "text": "The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1095432"}], "href": "https://doi.org/10.1126/science.1095432"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15073321"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15073321"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sophie Janssens, Antoine Tinel, Saskia Lippens, et al. 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