{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPoly(ADP‐ribose) polymerase‑1 (PARP1) is a highly abundant nuclear enzyme that functions as an early sensor of DNA damage and plays a central role in preserving genomic integrity. Upon encountering DNA single‐ or double‐strand breaks, PARP1 rapidly binds damaged chromatin and undergoes dramatic conformational changes–including an unfolding of its helical (HD) domain that relieves autoinhibition–thereby triggering its catalytic activation. This activation results in the synthesis of poly(ADP‑ribose) (PAR), which in turn promotes automodification, facilitates the recruitment of multiple repair factors, and orchestrates chromatin remodeling necessary for efficient repair. Structural studies have revealed that multiple PARP1 domains cooperate upon binding to DNA lesions, and biochemical analyses–complemented by genome‑wide screens–underscore its essential role in alternative end‑joining pathways and nucleotide excision repair, as well as in modulating local chromatin environments."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical role in DNA repair, PARP1 modulates transcription and replication dynamics through its ability to alter chromatin structure. By engaging with specific nucleosomal components and interacting with chromatin–binding domains present on factors such as macroH2A1.1 and the transcriptional co‐activator p300, PARP1 can orchestrate changes in histone composition and nucleosome accessibility. PARP1 also forms direct protein–protein interactions with oncogenic transcription factors such as ETS fusion proteins and with diverse chromatin remodelers (for example, Alc1), thereby impacting promoter usage, RNA polymerase II elongation, and the efficiency of replication fork progression. These multifaceted functions illustrate how PARP1 activity is interwoven with regulatory networks that govern transcriptional responses and genome replication."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in repair and transcription, PARP1 is a critical modulator of cell fate decisions that impact tumor biology and therapeutic response. Its overactivation can lead to a specialized form of caspase‑independent cell death (parthanatos), while its trapping on DNA under inhibitor treatment contributes to synthetic lethality in homologous recombination–deficient tumors. Moreover, PARP1 activity is implicated in the stabilization of mutant repair proteins, the development of drug resistance, and the modulation of immune signaling via pathways such as cGAS/STING and PD‑L1 regulation. These insights have underpinned the clinical development of PARP inhibitors as anticancer agents, both as monotherapies and in combination with other therapeutic modalities, and have fostered ongoing efforts to dissect and target PARP1‐dependent pathways in diverse disease contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marc Audebert, Bernard Salles, Patrick Calsou "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M404524200"}], "href": "https://doi.org/10.1074/jbc.M404524200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15498778"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15498778"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mi Young Kim, Steven Mauro, Nicolas Gévry, et al. 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