PARP (Poly ADP-ribose Polymerase) Family in Health and Disease

Abstract

The poly(ADP-ribose) polymerase (PARP) family consists of 17 members of nicotinamide adenine dinucleotide (NAD⁺)-dependent enzymes that regulate key biological processes by catalyzing adenosine diphosphate (ADP)-ribosylation, either poly(ADP-ribosyl)ation (PARylation) or mono(ADP-ribosyl)ation (MARylation). These biological processes encompass DNA repair, metabolism, telomere maintenance, and immune responses. Based on structural and functional features, the PARP family is classified into subcategories, such as DNA-dependent PARPs, Tankyrase, CCCH-type PARPs, MacroPARPs, and atypical PARPs. These enzymes dynamically maintain genome stability through mechanisms, including base excision repair and homologous recombination, while also regulating telomere dynamics and metabolic pathways. Dysregulation of PARP activity is implicated in the pathogenesis of diverse human diseases. Though PARP inhibitors have gained therapeutic interest in oncology, their wider roles in nononcological conditions, such as neurodegenerative diseases, cardiovascular disorders, and viral infections, remain poorly defined. This review elucidates the unique structural features of PARP family members and describes their multiple roles under physiological and pathological conditions, thus providing insights into treatment strategies. Additionally, it summarizes the advances and challenges in PARP-targeted therapies and explores future directions for innovative therapeutic approaches. The findings may serve as a valuable resource for informing both clinical research and drug development.

Keywords

PARP family / physiological functions / pathological mechanisms / DNA damage repair / metabolic regulation / PARP-targeted therapy

References

[1] D. D'Amours, S. Desnoyers, I. D'Silva, G. G. Poirier, “Poly(ADP-ribosyl)Ation Reactions in the Regulation of Nuclear Functions,” Biochemical Journal 342, no. Pt 2 (1999): 249-68.

[2] M. F. Langelier, J. L. Planck, S. Roy, J. M. Pascal, “Crystal Structures of Poly(ADP-ribose) Polymerase-1 (PARP-1) Zinc Fingers Bound to DNA: Structural and Functional Insights Into DNA-dependent PARP-1 Activity,” The Journal of Biological Chemistry 286, no. 12 (2011): 10690-701.

[3] M. G. Damale, S. K. Pathan, D. B. Shinde, R. H. Patil, R. B. Arote, J. N. Sangshetti, “Insights of Tankyrases: A Novel Target for Drug Discovery,” European Journal of Medicinal Chemistry 207 (2020): 112712.

[4] T. Todorova, F. J. Bock, P. Chang, “PARP13 regulates Cellular mRNA Post-transcriptionally and Functions as a Pro-apoptotic Factor by Destabilizing TRAILR4 Transcript,” Nature Communications 5 (2014): 5362.

[5] B. Lüscher, I. Ahel, M. Altmeyer, et al., “ADP-ribosyltransferases, an Update on Function and Nomenclature,” Febs Journal 289, no. 23 (2022): 7399-7410.

[6] L. Frigon, J. M. Pascal, “Structural and Biochemical Analysis of the PARP1-homology Region of PARP4/Vault PARP,” Nucleic Acids Research 51, no. 22 (2023): 12492-12507.

[7] J. Y. Huang, K. Wang, A. Vermehren-Schmaedick, J. P. Adelman, M. S. Cohen, “PARP6 is a Regulator of Hippocampal Dendritic Morphogenesis,” Scientific Reports 6 (2016): 18512.

[8] J. B. Khatib, A. Dhoonmoon, G. L. Moldovan, C. M. Nicolae, “PARP10 promotes the Repair of Nascent Strand DNA Gaps Through RAD18 Mediated Translesion Synthesis,” Nature Communications 15, no. 1 (2024): 6197.

[9] L. Li, Y. Shi, S. Li, et al., “ADP-ribosyltransferase PARP11 Suppresses Zika Virus in Synergy With PARP12,” Cell Biosci 11, no. 1 (2021): 116.

[10] S. Wang, M. Zhang, T. Li, et al., “A Comprehensively Prognostic and Immunological Analysis of PARP11 in Pan-cancer,” J Leukoc Biol 117, no. 1 (2024): qiae030.

[11] M. Jwa, P. Chang, “PARP16 is a Tail-anchored Endoplasmic Reticulum Protein Required for the PERK- and IRE1α-mediated Unfolded Protein Response,” Nature Cell Biology 14, no. 11 (2012): 1223-30.

[12] L. Frigon, J. M. Pascal, “Structural and Biochemical Analysis of the PARP1-homology Region of PARP4/Vault PARP,” Nucleic Acids Res. 51, no. 22 (2023): 12492-12507.

[13] A. Sefer, E. Kallis, T. Eilert, et al., “Structural Dynamics of DNA Strand Break Sensing by PARP-1 at a Single-molecule Level,” Nature Communications 13, no. 1 (2022): 6569.

[14] É. Rouleau-Turcotte, J. M. Pascal, “ADP-ribose Contributions to Genome Stability and PARP Enzyme Trapping on Sites of DNA Damage; Paradigm Shifts for a Coming-of-age Modification,” The Journal of Biological Chemistry 299, no. 12 (2023): 105397.

[15] I. Kalasova, R. Hailstone, J. Bublitz, et al., “Pathological Mutations in PNKP Trigger Defects in DNA Single-strand Break Repair but Not DNA Double-strand Break Repair,” Nucleic Acids Res. 48, no. 12 (2020): 6672-6684.

[16] C. A. Koczor, K. M. Saville, J. F. Andrews, et al., “Temporal Dynamics of Base Excision/Single-strand Break Repair Protein Complex Assembly/Disassembly Are Modulated by the PARP/NAD(+)/SIRT6 Axis,” Cell Reports 37, no. 5 (2021): 109917.

[17] A. Campalans, T. Kortulewski, R. Amouroux, H. Menoni, W. Vermeulen, J. P. Radicella, “Distinct Spatiotemporal Patterns and PARP Dependence of XRCC1 Recruitment to Single-strand Break and Base Excision Repair,” Nucleic Acids Res. 41, no. 5 (2013): 3115-29.

[18] M. J. Metzger, B. L. Stoddard, R. J. Monnat, “PARP-mediated Repair, Homologous Recombination, and Back-up Non-homologous End Joining-Like Repair of Single-strand Nicks,” Dna Repair 12, no. 7 (2013): 529-34.

[19] J. M. Lee, J. A. Ledermann, E. C. Kohn, “PARP Inhibitors for BRCA1/2 Mutation-associated and BRCA-Like Malignancies,” Annals of Oncology 25, no. 1 (2014): 32-40.

[20] H. Farmer, N. McCabe, C. J. Lord, et al., “Targeting the DNA Repair Defect in BRCA Mutant Cells as a Therapeutic Strategy,” Nature 434, no. 7035 (2005): 917-21.

[21] H. H. Y. Chang, N. R. Pannunzio, N. Adachi, M. R. Lieber, “Non-homologous DNA End Joining and Alternative Pathways to Double-strand Break Repair,” Nature Reviews Molecular Cell Biology 18, no. 8 (2017): 495-506.

[22] N. Pillay, L. Mariotti, M. Zaleska, et al., “Structural Basis of Tankyrase Activation by Polymerization,” Nature 612, no. 7938 (2022): 162-169.

[23] H. Zhang, M. H. Yang, J. J. Zhao, et al., “Inhibition of Tankyrase 1 in human Gastric Cancer Cells Enhances Telomere Shortening by Telomerase Inhibitors,” Oncology Reports 24, no. 4 (2010): 1059-65.

[24] J. Gao, J. Zhang, Y. Long, Y. Tian, X. Lu, “Expression of Tankyrase 1 in Gastric Cancer and Its Correlation With Telomerase Activity,” Pathology Oncology Research 17, no. 3 (2011): 685-90.

[25] S. Smith, I. Giriat, A. Schmitt, T. de Lange, “Tankyrase, a Poly(ADP-ribose) Polymerase at human Telomeres,” Science 282, no. 5393 (1998): 1484-7.

[26] M. S. Cohen, “Interplay Between Compartmentalized NAD(+) Synthesis and Consumption: A Focus on the PARP family,” Genes & development 34, no. 5-6 (2020): 254-262.

[27] D. Huang, Z. Su, Y. Mei, Z. Shao, “The Complex Universe of Inactive PARP1,” Trends in Genetics 40, no. 12 (2024): 1074-1085.

[28] M. M. Ge, J. J. Hu, Y. Q. Zhou, et al., “DNA Damage Induced PARP-1 Overactivation Confers Paclitaxel-induced Neuropathic Pain by Regulating Mitochondrial Oxidative Metabolism,” CNS neuroscience & therapeutics 30, no. 9 (2024): e70012.

[29] F. Shang, J. Zhang, Z. Li, et al., “Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade,” PLoS ONE 11, no. 3 (2016): e0151845.

[30] A. K. Hopp, P. Gruter, M. O. Hottiger, “Regulation of Glucose Metabolism by NAD(+) and ADP-Ribosylation,” Cells 8, no. 8 (2019): 890.

[31] H. Yako, N. Niimi, S. Takaku, A. Kato, K. Kato, K. Sango, “Role of Exogenous Pyruvate in Maintaining Adenosine Triphosphate Production Under High-Glucose Conditions Through PARP-Dependent Glycolysis and PARP-Independent Tricarboxylic Acid Cycle,” International Journal of Molecular Sciences 25, no. 20 (2024): 11089.

[32] K. Devalaraja-Narashimha, B. J. Padanilam, “PARP1 deficiency Exacerbates Diet-induced Obesity in Mice,” Journal of Endocrinology 205, no. 3 (2010): 243-52.

[33] K. W. Ryu, T. Nandu, J. Kim, S. Challa, R. J. DeBerardinis, W. L. Kraus, “Metabolic Regulation of Transcription Through Compartmentalized NAD(+) Biosynthesis,” Science 360, no. 6389 (2018): eaan5780.

[34] G. Lee, Y. Y. Kim, H. Jang, et al., “SREBP1c-PARP1 axis Tunes Anti-senescence Activity of Adipocytes and Ameliorates Metabolic Imbalance in Obesity,” Cell metabolism 34, no. 5 (2022): 702-718. e5.

[35] L. Zhu, Z. Xie, G. Yang, G. Zhou, L. Li, S. Zhang, “Stanniocalcin-1 Promotes PARP1-Dependent Cell Death via JNK Activation in Colitis,” Advanced Science (Weinheim, Baden-Wurttemberg, Germany) 11, no. 5 (2024): e2304123.

[36] S. Krug, M. Gupta, P. Kumar, et al., “Inhibition of Host PARP1 Contributes to the Anti-inflammatory and Antitubercular Activity of Pyrazinamide,” Nature Communications 14, no. 1 (2023): 8161.

[37] S. Lin, G. Tu, Z. Yu, et al., “Discovery of CN0 as a Novel Proteolysis-targeting Chimera (PROTAC) Degrader of PARP1 That Can Activate the cGAS/STING Immunity Pathway Combined With Daunorubicin,” Bioorganic & Medicinal Chemistry 70 (2022): 116912.

[38] X. Peng, W. Pan, F. Jiang, et al., “Selective PARP1 Inhibitors, PARP1-based Dual-target Inhibitors, PROTAC PARP1 Degraders, and Prodrugs of PARP1 Inhibitors for Cancer Therapy,” Pharmacological Research 186 (2022): 106529.

[39] M. L. Hu, Y. R. Pan, Y. Y. Yong, et al., “Poly (ADP-ribose) Polymerase 1 and Neurodegenerative Diseases: Past, Present, and Future,” Ageing Research Reviews 91 (2023): 102078.

[40] X. Xu, B. Sun, C. Zhao, “Poly (ADP-Ribose) Polymerase 1 and Parthanatos in Neurological Diseases: From Pathogenesis to Therapeutic Opportunities,” Neurobiology of Disease 187 (2023): 106314.

[41] J. Sun, G. Liu, R. Chen, et al., “PARP1 Is Upregulated by Hyperglycemia via N6-methyladenosine Modification and Promotes Diabetic Retinopathy,” Discovery Medicine 34, no. 172 (2022): 115-129.

[42] X. Sun, H. Tang, Y. Chen, et al., “Loss of the Receptors ER, PR and HER2 Promotes USP15-dependent Stabilization of PARP1 in Triple-negative Breast Cancer,” Nat Cancer 4, no. 5 (2023): 716-733.

[43] X. Zhang, Q. Zhao, T. Wang, et al., “DNA Damage Response, a Double-edged Sword for Vascular Aging,” Ageing Research Reviews 92 (2023): 102137.

[44] H. Sun, C. Liu, F. Han, et al., “The Regulation Loop of MARVELD1 Interacting With PARP1 in DNA Damage Response Maintains Genome Stability and Promotes Therapy Resistance of Cancer Cells,” Cell Death and Differentiation 30, no. 4 (2023): 922-937.

[45] M. A. Galindo-Campos, N. Lutfi, S. Bonnin, et al., “Distinct Roles for PARP-1 and PARP-2 in c-Myc-driven B-cell Lymphoma in Mice,” Blood 139, no. 2 (2022): 228-239.

[46] C. T. Guy, R. D. Cardiff, W. J. Muller, “Induction of Mammary Tumors by Expression of Polyomavirus Middle T Oncogene: A Transgenic Mouse Model for Metastatic Disease,” Molecular and Cellular Biology 12, no. 3 (1992): 954-61.

[47] H. Zuo, D. Yang, Q. Yang, H. Tang, Y. X. Fu, Y. Wan, “Differential Regulation of Breast Cancer Bone Metastasis by PARP1 and PARP2,” Nature Communications 11, no. 1 (2020): 1578.

[48] J. P. Gagné, C. Ethier, D. Defoy, et al., “Quantitative Site-specific ADP-ribosylation Profiling of DNA-dependent PARPs,” DNA Repair 30 (2015): 68-79.

[49] M.-F. Langelier, D. D. Ruhl, J. L. Planck, W. L. Kraus, J. M. Pascal, “The Zn3 Domain of human Poly(ADP-ribose) Polymerase-1 (PARP-1) Functions in both DNA-dependent Poly(ADP-ribose) Synthesis Activity and Chromatin Compaction,” The Journal of Biological Chemistry 285, no. 24 (2010): 18877-87.

[50] Z. Tao, P. Gao, H.-W. Liu, “Identification of the ADP-ribosylation Sites in the PARP-1 Automodification Domain: Analysis and Implications,” Journal of the American Chemical Society 131, no. 40 (2009): 14258-60.

[51] M. Altmeyer, S. Messner, P. O. Hassa, M. Fey, M. O. Hottiger, “Molecular Mechanism of Poly(ADP-ribosyl)Ation by PARP1 and Identification of Lysine Residues as ADP-ribose Acceptor Sites,” Nucleic Acids Res. 37, no. 11 (2009): 3723-38.

[52] C. J. Lord, A. Ashworth, “PARP Inhibitors: Synthetic Lethality in the Clinic,” Science 355, no. 6330 (2017): 1152-1158.

[53] L. Palazzo, I. Ahel, “PARPs in Genome Stability and Signal Transduction: Implications for Cancer Therapy,” Biochemical Society Transactions 46, no. 6 (2018): 1681-1695.

[54] H. Mendoza-Alvarez, R. Alvarez-Gonzalez, “Poly(ADP-ribose) Polymerase Is a Catalytic Dimer and the Automodification Reaction Is Intermolecular,” The Journal of Biological Chemistry 268, no. 30 (1993): 22575-80.

[55] J. C. Ame, V. Rolli, V. Schreiber, et al., “PARP-2, a Novel Mammalian DNA Damage-dependent Poly(ADP-ribose) Polymerase,” The Journal of Biological Chemistry 274, no. 25 (1999): 17860-8.

[56] M. Szanto, A. Brunyanszki, B. Kiss, et al., “Poly(ADP-ribose) Polymerase-2: Emerging Transcriptional Roles of a DNA-repair Protein,” Cellular and Molecular Life Sciences: CMLS 69, no. 24 (2012): 4079-92.

[57] L. van Beek, E. McClay, S. Patel, M. Schimpl, L. Spagnolo, T. Maia De Oliveira, “PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling,” International Journal of Molecular Sciences 22, no. 10 (2021): 5112.

[58] L. Zimmerlin, E. T. Zambidis, “Pleiotropic Roles of Tankyrase/PARP Proteins in the Establishment and Maintenance of human Naive Pluripotency,” Experimental Cell Research 390, no. 1 (2020): 111935.

[59] D. Xu, J. Liu, T. Fu, et al., “USP25 regulates Wnt Signaling by Controlling the Stability of Tankyrases,” Genes & development 31, no. 10 (2017): 1024-1035.

[60] B. Luscher, I. Ahel, M. Altmeyer, et al., “ADP-ribosyltransferases, an Update on Function and Nomenclature,” Febs Journal 289, no. 23 (2022): 7399-7410.

[61] G. I. Karras, G. Kustatscher, H. R. Buhecha, et al., “The Macro Domain Is an ADP-ribose Binding Module,” The EMBO Journal 24, no. 11 (2005): 1911-20.

[62] H. Iwata, C. Goettsch, A. Sharma, et al., “PARP9 and PARP14 Cross-regulate Macrophage Activation via STAT1 ADP-ribosylation,” Nature Communications 7, no. 1 (2016): 12849.

[63] N. Đukić, Ø. Strømland, J. D. Elsborg, et al., “PARP14 is a PARP With both ADP-ribosyl Transferase and Hydrolase Activities,” Science Advances 9, no. 37 (2023): eadi2687.

[64] M. Jwa, P. Chang, “PARP16 is a Tail-anchored Endoplasmic Reticulum Protein Required for the PERK- and IRE1alpha-mediated Unfolded Protein Response,” Nature Cell Biology 14, no. 11 (2012): 1223-30.

[65] J. Wang, J. Xu, Y. Dong, et al., “ADP-ribose Transferase PARP16 Mediated-unfolded Protein Response Contributes to Neuronal Cell Damage in Cerebral Ischemia/Reperfusion,” FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 37, no. 2 (2023): e22788.

[66] J. Yelamos, V. Schreiber, F. Dantzer, “Toward Specific Functions of Poly(ADP-ribose) Polymerase-2,” Trends in Molecular Medicine 14, no. 4 (2008): 169-78.

[67] O. Mortusewicz, J.-C. Ame, V. Schreiber, H. Leonhardt, “Feedback-regulated Poly(ADP-ribosyl)Ation by PARP-1 Is Required for Rapid Response to DNA Damage in Living Cells,” Nucleic Acids Res. 35, no. 22 (2007): 7665-75.

[68] A. A. Riccio, G. Cingolani, J. M. Pascal, “PARP-2 Domain Requirements for DNA Damage-dependent Activation and Localization to Sites of DNA Damage,” Nucleic Acids Res. 44, no. 4 (2016): 1691-702.

[69] S. F. El-Khamisy, M. Masutani, H. Suzuki, K. W. Caldecott, “A Requirement for PARP-1 for the Assembly or Stability of XRCC1 Nuclear Foci at Sites of Oxidative DNA Damage,” Nucleic Acids Res. 31, no. 19 (2003): 5526-33.

[70] C. Boehler, L. R. Gauthier, O. Mortusewicz, et al., “Poly(ADP-ribose) Polymerase 3 (PARP3), a Newcomer in Cellular Response to DNA Damage and Mitotic Progression,” Proceedings of the National Academy of Sciences of the United States of America 108, no. 7 (2011): 2783-8.

[71] Z. Li, Y. Yamauchi, M. Kamakura, et al., “Herpes simplex Virus Requires Poly(ADP-ribose) Polymerase Activity for Efficient Replication and Induces Extracellular Signal-related Kinase-dependent Phosphorylation and ICP0-dependent Nuclear Localization of Tankyrase 1,” Journal of Virology 86, no. 1 (2012): 492-503.

[72] W. Chang, J. N. Dynek, S. Smith, “NuMA Is a Major Acceptor of Poly(ADP-ribosyl)Ation by Tankyrase 1 in Mitosis,” Biochemical Journal 391, no. Pt 2 (2005): 177-84.

[73] J. Perrard, S. Smith, “Multiple E3 Ligases Control Tankyrase Stability and Function,” Nature Communications 14, no. 1 (2023): 7208.

[74] A. Derevyanko, K. Whittemore, R. P. Schneider, V. Jimenez, F. Bosch, M. A. Blasco, “Gene Therapy With the TRF1 Telomere Gene Rescues Decreased TRF1 Levels With Aging and Prolongs Mouse Health Span,” Aging Cell 16, no. 6 (2017): 1353-1368.

[75] S. Smith, T. de Lange, “Tankyrase Promotes Telomere Elongation in human Cells,” Current Biology 10, no. 20 (2000): 1299-302.

[76] G.-H. Ha, H.-S. Kim, H. Go, et al., “Tankyrase-1 Function at Telomeres and During Mitosis Is Regulated by Polo-Like Kinase-1-mediated Phosphorylation,” Cell Death and Differentiation 19, no. 2 (2012): 321-332.

[77] A. Lyakhovich, M. J. Ramirez, A. Castellanos, et al., “Fanconi Anemia Protein FANCD2 Inhibits TRF1 polyADP-ribosylation Through tankyrase1-dependent Manner,” Genome Integr 2, no. 1 (2011): 4.

[78] L. Mariotti, C. M. Templeton, M. Ranes, et al., “Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-beta-Catenin Signaling,” Molecular Cell 63, no. 3 (2016): 498-513.

[79] A. Gomez, C. Bindesboll, S. V. Satheesh, et al., “Characterization of TCDD-inducible Poly-ADP-ribose Polymerase (TIPARP/ARTD14) Catalytic Activity,” Biochemical Journal 475, no. 23 (2018): 3827-3846.

[80] L. Zhang, J. Cao, L. Dong, H. Lin, “TiPARP Forms Nuclear Condensates to Degrade HIF-1alpha and Suppress Tumorigenesis,” Proceedings of the National Academy of Sciences of the United States of America 117, no. 24 (2020): 13447-13456.

[81] G. Catara, G. Grimaldi, L. Schembri, et al., “PARP1-produced Poly-ADP-ribose Causes the PARP12 Translocation to Stress Granules and Impairment of Golgi Complex Functions,” Scientific Reports 7, no. 1 (2017): 14035.

[82] V. F. Busa, Y. Ando, S. Aigner, B. A. Yee, G. W. Yeo, A. Leung, “Transcriptome Regulation by PARP13 in Basal and Antiviral States in human Cells,” Iscience 27, no. 4 (2024): 109251.

[83] T. Karlberg, M. Klepsch, A. G. Thorsell, C. D. Andersson, A. Linusson, H. Schuler, “Structural Basis for Lack of ADP-ribosyltransferase Activity in Poly(ADP-ribose) Polymerase-13/Zinc Finger Antiviral Protein,” The Journal of Biological Chemistry 290, no. 12 (2015): 7336-44.

[84] J. Xing, A. Zhang, Y. Du, et al., “Identification of Poly(ADP-ribose) Polymerase 9 (PARP9) as a Noncanonical Sensor for RNA Virus in Dendritic Cells,” Nature Communications 12, no. 1 (2021): 2681.

[85] P. Kar, C. Chatrin, N. Dukic, et al., “PARP14 and PARP9/DTX3L Regulate Interferon-induced ADP-ribosylation,” The EMBO Journal 43, no. 14 (2024): 2929-2953.

[86] X. Zhou, Y. Yang, Q. Xu, et al., “Crystal Structures of the Catalytic Domain of human PARP15 in Complex With Small Molecule Inhibitors,” Biochemical and Biophysical Research Communications 622 (2022): 93-100.

[87] E. Rouleau-Turcotte, J. M. Pascal, “ADP-ribose Contributions to Genome Stability and PARP Enzyme Trapping on Sites of DNA Damage; Paradigm Shifts for a Coming-of-age Modification,” The Journal of Biological Chemistry 299, no. 12 (2023): 105397.

[88] R. Brem, J. Hall, “XRCC1 is Required for DNA Single-strand Break Repair in human Cells,” Nucleic Acids Res. 33, no. 8 (2005): 2512-20.

[89] J. T. Heale, A. J. Ball, J. A. Schmiesing, et al., “Condensin I Interacts With the PARP-1-XRCC1 Complex and Functions in DNA Single-strand Break Repair,” Molecular Cell 21, no. 6 (2006): 837-48.

[90] S. Paradkar, J. Purcell, A. Cui, et al., “PARG Inhibition Induces Nuclear Aggregation of PARylated PARP1,” Structure (London, England) 32, no. 11 (2024): 2083-2093. e5.

[91] E. Gogola, A. A. Duarte, J. R. de Ruiter, et al., “Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality,” Cancer Cell 33, no. 6 (2018): 1078-1093. e12.

[92] U. Vekariya, L. Minakhin, G. Chandramouly, et al., “PARG Is Essential for Poltheta-mediated DNA End-joining by Removing Repressive Poly-ADP-ribose Marks,” Nature Communications 15, no. 1 (2024): 5822.

[93] H. Gao, D. L. Coyle, M. L. Meyer-Ficca, et al., “Altered Poly(ADP-ribose) Metabolism Impairs Cellular Responses to Genotoxic Stress in a Hypomorphic Mutant of Poly(ADP-ribose) Glycohydrolase,” Experimental Cell Research 313, no. 5 (2007): 984-96.

[94] S. Oka, J. Kato, J. Moss, “Identification and Characterization of a Mammalian 39-kDa Poly(ADP-ribose) Glycohydrolase,” The Journal of Biological Chemistry 281, no. 2 (2006): 705-13.

[95] Y. Gao, C. Li, L. Wei, et al., “SSRP1 Cooperates With PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming,” Cancer Research 77, no. 10 (2017): 2674-2685.

[96] C. G. O'Sullivan, C. Karlovich, D. Wilsker, et al., “PARP Inhibitor Applicability: Detailed Assays for Homologous Recombination Repair Pathway Components,” Onco Targets Ther 15 (2022): 165-180.

[97] S. Xie, O. Mortusewicz, H. T. Ma, et al., “Timeless Interacts With PARP-1 to Promote Homologous Recombination Repair,” Molecular Cell 60, no. 1 (2015): 163-76.

[98] C. Moison, J. Chagraoui, M. C. Caron, et al., “Zinc Finger Protein E4F1 Cooperates With PARP-1 and BRG1 to Promote DNA Double-strand Break Repair,” Proceedings of the National Academy of Sciences of the United States of America 118, no. 11 (2021): e2019408118.

[99] J. R. Chapman, P. Barral, J. B. Vannier, et al., “RIF1 is Essential for 53BP1-dependent Nonhomologous End Joining and Suppression of DNA Double-strand Break Resection,” Molecular Cell 49, no. 5 (2013): 858-71.

[100] W. Jacot, S. Thezenas, R. Senal, et al., “BRCA1 promoter Hypermethylation, 53BP1 Protein Expression and PARP-1 Activity as Biomarkers of DNA Repair Deficit in Breast Cancer,” BMC cancer 13 (2013): 523.

[101] H. Chang, N. R. Pannunzio, N. Adachi, M. R. Lieber, “Non-homologous DNA End Joining and Alternative Pathways to Double-strand Break Repair,” Nature Reviews Molecular Cell Biology 18, no. 8 (2017): 495-506.

[102] N. R. Pannunzio, S. Li, G. Watanabe, M. R. Lieber, “Non-homologous End Joining Often Uses Microhomology: Implications for Alternative End Joining,” Dna Repair 17 (2014): 74-80.

[103] P. E. Head, P. Kapoor-Vazirani, G. P. Nagaraju, et al., “DNA-PK Is Activated by SIRT2 Deacetylation to Promote DNA Double-strand Break Repair by Non-homologous End Joining,” Nucleic Acids Res. 51, no. 15 (2023): 7972-7987.

[104] Q. Cheng, N. Barboule, P. Frit, et al., “Ku Counteracts Mobilization of PARP1 and MRN in Chromatin Damaged With DNA Double-strand Breaks,” Nucleic Acids Res. 39, no. 22 (2011): 9605-19.

[105] J. Ma, Y. Zhou, P. Pan, et al., “TRABID Overexpression Enables Synthetic Lethality to PARP Inhibitor via Prolonging 53BP1 Retention at Double-strand Breaks,” Nature Communications 14, no. 1 (2023): 1810.

[106] R. Gupta, K. Somyajit, T. Narita, et al., “DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity,” Cell 173, no. 4 (2018): 972-988. e23.

[107] N. Chappidi, T. Quail, S. Doll, et al., “PARP1-DNA co-condensation Drives DNA Repair Site Assembly to Prevent Disjunction of Broken DNA Ends,” Cell 187, no. 4 (2024): 945-961. e18.

[108] J. Gao, J. Zhang, Y. Long, Y. Tian, X. Lu, “Expression of Tankyrase 1 in Gastric Cancer and Its Correlation With Telomerase Activity,” Pathology Oncology Research : POR 17, no. 3 (2011): 685-90.

[109] T. Pankotai, C. Bonhomme, D. Chen, E. Soutoglou, “DNAPKcs-dependent Arrest of RNA Polymerase II Transcription in the Presence of DNA Breaks,” Nature structural & molecular biology 19, no. 3 (2012): 276-82.

[110] R. C. Dregalla, J. Zhou, R. R. Idate, C. L. Battaglia, H. L. Liber, S. M. Bailey, “Regulatory Roles of Tankyrase 1 at Telomeres and in DNA Repair: Suppression of T-SCE and Stabilization of DNA-PKcs,” Aging (Albany NY) 2, no. 10 (2010): 691-708.

[111] P. Chang, M. Coughlin, T. J. Mitchison, “Tankyrase-1 Polymerization of Poly(ADP-ribose) Is Required for Spindle Structure and Function,” Nature Cell Biology 7, no. 11 (2005): 1133-9.

[112] D. JN, S. S, “Resolution of Sister Telomere Association Is Required for Progression Through Mitosis,” Science (New York, NY) 304, no. 5667 (2004): 97-100.

[113] Z. Daniloski, K. K. Bisht, B. McStay, S. Smith, “Resolution of human Ribosomal DNA Occurs in Anaphase, Dependent on Tankyrase 1, Condensin II, and Topoisomerase IIα,” Genes & development 33, no. 5-6 (2019): 276-281.

[114] V. Sagathia, C. Patel, J. Beladiya, S. Patel, D. Sheth, G. Shah, “Tankyrase: A Promising Therapeutic Target With Pleiotropic Action,” Naunyn-Schmiedebergs Archives of Pharmacology 396, no. 12 (2023): 3363-3374.

[115] S. Beneke, O. Cohausz, M. Malanga, P. Boukamp, F. Althaus, A. Bürkle, “Rapid Regulation of Telomere Length Is Mediated by Poly(ADP-ribose) Polymerase-1,” Nucleic Acids Res. 36, no. 19 (2008): 6309-17.

[116] E. Samper, F. A. Goytisolo, J. Ménissier-de Murcia, et al., “Normal Telomere Length and Chromosomal End Capping in Poly(ADP-ribose) Polymerase-deficient Mice and Primary Cells Despite Increased Chromosomal Instability,” Journal of Cell Biology 154, no. 1 (2001): 49-60.

[117] U. Ghosh, N. Das, N. P. Bhattacharyya, “Inhibition of Telomerase Activity by Reduction of Poly(ADP-ribosyl)Ation of TERT and TEP1/TP1 Expression in HeLa Cells With Knocked Down Poly(ADP-ribose) Polymerase-1 (PARP-1) Gene,” Mutation Research 615, no. 1-2 (2007): 66-74.

[118] D. Huang, W. L. Kraus, “The Expanding Universe of PARP1-mediated Molecular and Therapeutic Mechanisms,” Molecular Cell 82, no. 12 (2022): 2315-2334.

[119] R. Gupte, Z. Liu, W. L. Kraus, “PARPs and ADP-ribosylation: Recent Advances Linking Molecular Functions to ,” Genes & development 31, no. 2 (2017): 101-126.

[120] A. Y.-T. Wu, P. Sekar, D.-Y. Huang, S.-H. Hsu, C.-M. Chan, W.-W. Lin, “Spatiotemporal Roles of AMPK in PARP-1- and Autophagy-dependent Retinal Pigment Epithelial Cell Death Caused by UVA,” Journal of Biomedical Science 30, no. 1 (2023): 91.

[121] H. Zhu, Z. Fang, J. Chen, et al., “PARP-1 and SIRT-1 Are Interacted in Diabetic Nephropathy by Activating AMPK/PGC-1α Signaling Pathway,” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 14 (2021): 355-366.

[122] T. Nishida, I. Naguro, H. Ichijo, “NAMPT-dependent NAD + Salvage Is Crucial for the Decision Between Apoptotic and Necrotic Cell Death Under Oxidative Stress,” Cell Death Discov 8, no. 1 (2022): 195.

[123] F. J. Martínez-Morcillo, J. Cantón-Sandoval, F. J. Martínez-Navarro, et al., “NAMPT-derived NAD+ Fuels PARP1 to Promote Skin Inflammation Through Parthanatos Cell Death,” PLoS Biology 19, no. 11 (2021): e3001455.

[124] Y. Dai, J. Lin, X. Chen, et al., “NAMPT/NAD + /PARP1 Pathway Regulates CFA-Induced Inflammatory Pain via NF-κB Signaling in Rodents,” Advanced Biology 8, no. 5 (2024): e2400028.

[125] K. Devalaraja-Narashimha, B. J. Padanilam, “PARP-1 Inhibits Glycolysis in Ischemic Kidneys,” Journal of the American Society of Nephrology 20, no. 1 (2009): 95-103.

[126] S. W. Suh, K. Aoyama, Y. Matsumori, J. Liu, R. A. Swanson, “Pyruvate Administered After Severe Hypoglycemia Reduces Neuronal Death and Cognitive Impairment,” Diabetes 54, no. 5 (2005): 1452-8.

[127] H.-L. Guo, C. Zhang, Q. Liu, et al., “The Axin/TNKS Complex Interacts With KIF3A and Is Required for Insulin-stimulated GLUT4 Translocation,” Cell Research 22, no. 8 (2012): 1246-57.

[128] T.-Y. J. Yeh, J. I. Sbodio, Z.-Y. Tsun, B. Luo, N.-W. Chi, “Insulin-stimulated Exocytosis of GLUT4 Is Enhanced by IRAP and Its Partner Tankyrase,” Biochemical Journal 402, no. 2 (2007): 279-90.

[129] J. Marton, T. Fodor, L. Nagy, et al., “PARP10 (ARTD10) modulates Mitochondrial Function,” PLoS ONE 13, no. 1 (2018): e0187789.

[130] S. H. Cho, A. K. Ahn, P. Bhargava, et al., “Glycolytic Rate and Lymphomagenesis Depend on PARP14, an ADP Ribosyltransferase of the B Aggressive Lymphoma (BAL) family,” Proceedings of the National Academy of Sciences of the United States of America 108, no. 38 (2011): 15972-7.

[131] L. Xu, Y. Ma, Y. Ji, et al., “Obesity Exacerbates Postoperative Cognitive Dysfunction by Activating the PARP1/NAD(+)/SIRT1 Axis Through Oxidative Stress,” Experimental Gerontology (2023): 112320.

[132] M. Jhanji, C. N. Rao, J. C. Massey, et al., “Cis- and Trans-resveratrol Have Opposite Effects on Histone Serine-ADP-ribosylation and Tyrosine Induced Neurodegeneration,” Nature Communications 13, no. 1 (2022): 3244.

[133] Z. Lengyel-Zhand, L. N. Puentes, R. H. Mach, “PARkinson's: From Cellular Mechanisms to Potential Therapeutics,” Pharmacology & Therapeutics 230 (2022): 107968.

[134] J. Zhang, X. Hu, Y. Geng, et al., “Exploring the Role of Parthanatos in CNS Injury: Molecular Insights and Therapeutic Approaches,” Journal of Advanced Research 70 (2024): 271-286.

[135] M. Szántó, J. Yélamos, P. Bai, “Specific and Shared Biological Functions of PARP2 - is PARP2 Really a Lil' brother of PARP1?,” Expert Reviews in Molecular Medicine 26 (2024): e13.

[136] Y. F. Lee, C. Z. J. Phua, J. Yuan, et al., “PARP4 interacts With hnRNPM to Regulate Splicing During Lung Cancer Progression,” Genome Medicine 16, no. 1 (2024): 91.

[137] J. Wu, D. L. Crowe, “PARP5B is Required for Nonhomologous End Joining During Tumorigenesis in Vivo,” Molecular Carcinogenesis 61, no. 1 (2021): 85-98.

[138] Q. Chen, X. He, B. Li, J. Chen, X. Tang, S. Yang, “Suppression of Long Noncoding RNA SNHG1 Inhibits the Development of Hypopharyngeal Squamous Cell Carcinoma via Increasing PARP6 Expression,” Evidence-Based Complementary and Alternative Medicine 2022 (2022): 1-10.

[139] B. Tang, Y. Zhang, W. Wang, G. Qi, F. Shimamoto, “PARP6 suppresses the Proliferation and Metastasis of Hepatocellular Carcinoma by Degrading XRCC6 to Regulate the Wnt/β-catenin Pathway,” American Journal of Cancer Research 10, no. 7 (2020): 2100-2113.

[140] F. Naulin, E. Guilbaud, L. Galluzzi, “PARP7 and Nucleic Acid-driven Oncosuppression,” Cellular & Molecular Immunology 21, no. 11 (2024): 1177-1179.

[141] E. M. Schleicher, A. M. Galvan, Y. Imamura-Kawasawa, G.-L. Moldovan, C. M. Nicolae, “PARP10 promotes Cellular Proliferation and Tumorigenesis by Alleviating Replication Stress,” Nucleic Acids Research 46, no. 17 (2018): 8908-8916.

[142] Y. Zhao, X. Hu, L. Wei, et al., “PARP10 suppresses Tumor Metastasis Through Regulation of Aurora A Activity,” Oncogene 37, no. 22 (2018): 2921-2935.

[143] H. Zhang, P. Yu, V. S. Tomar, et al., “Targeting PARP11 to Avert Immunosuppression and Improve CAR T Therapy in Solid Tumors,” Nat Cancer 3, no. 7 (2022): 808-820.

[144] R. Basavaraja, H. Zhang, Á. Holczbauer, et al., “PARP11 inhibition Inactivates Tumor-infiltrating Regulatory T Cells and Improves the Efficacy of Immunotherapies,” Cell Reports Medicine 5, no. 7 (2024): 101649.

[145] C. Shao, Y. Qiu, J. Liu, et al., “PARP12 (ARTD12) suppresses Hepatocellular Carcinoma Metastasis Through Interacting With FHL2 and Regulating Its Stability,” Cell Death & Disease 9, no. 9 (2018): 856.

[146] J.-Y. Im, S. J. Kim, J.-L. Park, et al., “CYB5R3 functions as a Tumor Suppressor by Inducing ER Stress-mediated Apoptosis in Lung Cancer Cells via the PERK-ATF4 and IRE1α-JNK Pathways,” Experimental & Molecular Medicine 56, no. 1 (2024): 235-249.

[147] A. Vermehren-Schmaedick, J. Y. Huang, M. Levinson, et al., “Characterization of PARP6 Function in Knockout Mice and Patients With Developmental Delay,” Cells 10, no. 6 (2021): 1289.

[148] J. Wang, Q. Cheng, Y. Zhang, et al., “PARP16-Mediated Stabilization of Amyloid Precursor Protein mRNA Exacerbates Alzheimer's Disease Pathogenesis,” Aging and Disease 14, no. 4 (2023): 1458-1471.

[149] W. Yu, X. Li, C. Zhang, et al., “KDM6B knockdown Alleviates Sleep Deprivation-induced Cerebrovascular Lesions in APP/PS1 Mice by Inhibiting PARP16 Expression,” Biochemical Pharmacology 231 (2025): 116650.

[150] N. Chen, L. Zhang, Z. Zhong, et al., “PARP9 affects Myocardial Function Through TGF-β/Smad Axis and Pirfenidone,” Biomolecules and Biomedicine 24, no. 5 (2024): 1199-1215.

[151] X.-Q. Gao, Y.-H. Zhang, F. Liu, et al., “The piRNA CHAPIR Regulates Cardiac Hypertrophy by Controlling METTL3-dependent N6-methyladenosine Methylation of Parp10 mRNA,” Nature Cell Biology 22, no. 11 (2020): 1319-1331.

[152] H. Su, J. Xu, Z. Su, et al., “Poly (ADP-ribose) Polymerases 16 Triggers Pathological Cardiac Hypertrophy via Activating IRE1α-sXBP1-GATA4 Pathway,” Cellular and Molecular Life Sciences : CMLS 80, no. 6 (2023): 161.

[153] D. Antal, Á. Pór, I. Kovács, et al., “PARP2 promotes Inflammation in Psoriasis by Modulating Estradiol Biosynthesis in Keratinocytes,” Journal of Molecular Medicine (Berlin, Germany) 101, no. 8 (2023): 987-999.

[154] M. Bencsics, B. Bányai, H. Ke, et al., “PARP2 downregulation in T Cells Ameliorates Lipopolysaccharide-induced Inflammation of the Large Intestine,” Frontiers in Immunology 14 (2023): 1135410.

[155] K. W. Bock, “Aryl Hydrocarbon Receptor (AHR) Functions in Infectious and Sterile Inflammation and NAD + -dependent Metabolic Adaptation,” Archives of Toxicology 95, no. 11 (2021): 3449-3458.

[156] H. Zhu, L. F. Wu, X. B. Mo, et al., “Rheumatoid Arthritis-associated DNA Methylation Sites in Peripheral Blood Mononuclear Cells,” Annals of the Rheumatic Diseases 78, no. 1 (2019): 36-42.

[157] Z. Deng, D. Long, C. Li, et al., “IRF1-mediated Upregulation of PARP12 Promotes Cartilage Degradation by Inhibiting PINK1/Parkin Dependent Mitophagy Through ISG15 Attenuating Ubiquitylation and SUMOylation of MFN1/2,” Bone Research 12, no. 1 (2024): 63.

[158] F. Wang, M. Zhao, B. Chang, et al., “Cytoplasmic PARP1 Links the Genome Instability to the Inhibition of Antiviral Immunity Through PARylating cGAS,” Molecular Cell 82, no. 11 (2022): 2032-2049. e7.

[159] P. Kar, C. Chatrin, N. Đukić, et al., “PARP14 and PARP9/DTX3L Regulate Interferon-induced ADP-ribosylation,” The EMBO Journal 43, no. 14 (2024): 2929-2953.

[160] S. Krieg, F. Pott, L. Potthoff, et al., “Mono-ADP-ribosylation by PARP10 Inhibits Chikungunya Virus nsP2 Proteolytic Activity and Viral Replication,” Cellular and Molecular Life Sciences : CMLS 80, no. 3 (2023): 72.

[161] L. Li, H. Zhao, P. Liu, et al., “PARP12 suppresses Zika Virus Infection Through PARP-dependent Degradation of NS1 and NS3 Viral Proteins,” Science Signaling 11, no. 535 (2018): eaas9332.

[162] T. Guo, Y. Zuo, L. Qian, et al., “ADP-ribosyltransferase PARP11 Modulates the Interferon Antiviral Response by Mono-ADP-ribosylating the Ubiquitin E3 Ligase β-TrCP,” Nature Microbiology 4, no. 11 (2019): 1872-1884.

[163] C. M. Kerr, S. Parthasarathy, N. Schwarting, et al., “PARP12 is Required to Repress the Replication of a Mac1 Mutant Coronavirus in a Cell- and Tissue-specific Manner,” Journal of Virology 97, no. 9 (2023): e0088523.

[164] V. F. Busa, Y. Ando, S. Aigner, B. A. Yee, G. W. Yeo, A. K. L. Leung, “Transcriptome Regulation by PARP13 in Basal and Antiviral States in human Cells,” Iscience 27, no. 4 (2024): 109251.

[165] D. Hanahan, “Hallmarks of Cancer: New Dimensions,” Cancer Discovery 12, no. 1 (2022): 31-46.

[166] X. Sun, H. Tang, Y. Chen, et al., “Loss of the Receptors ER, PR and HER2 Promotes USP15-dependent Stabilization of PARP1 in Triple-negative Breast Cancer,” Nature Cancer 4, no. 5 (2023): 716-733.

[167] J. Lin, Y. Yin, J. Cao, et al., “Nudix Hydrolase 13 Impairs the Initiation of Colorectal Cancer by Inhibiting PKM1 ADP-Ribosylation,” Advanced Science (Weinheim, Baden-Wurttemberg, Germany) 12, no. 13 (2025): e2410058.

[168] P. Huang, G. Chen, W. Jin, K. Mao, H. Wan, Y. He, “Molecular Mechanisms of Parthanatos and Its Role in Diverse Diseases,” International Journal of Molecular Sciences 23, no. 13 (2022): 7292.

[169] C. Pu, Y. Tong, Y. Liu, et al., “Selective Degradation of PARP2 by PROTACs via Recruiting DCAF16 for Triple-negative Breast Cancer,” European Journal of Medicinal Chemistry 236 (2022): 114321.

[170] B. Gui, F. Gui, T. Takai, et al., “Selective Targeting of PARP-2 Inhibits Androgen Receptor Signaling and Prostate Cancer Growth Through Disruption of FOXA1 Function,” Proceedings of the National Academy of Sciences of the United States of America 116, no. 29 (2019): 14573-14582.

[171] F. Moroni, L. Formentini, E. Gerace, et al., “Selective PARP-2 Inhibitors Increase Apoptosis in Hippocampal Slices but Protect Cortical Cells in Models of Post-ischaemic Brain Damage,” British Journal of Pharmacology 157, no. 5 (2009): 854-862.

[172] A. Kamboj, P. Lu, M. B. Cossoy, et al., “Poly(ADP-ribose) Polymerase 2 Contributes to Neuroinflammation and Neurological Dysfunction in Mouse Experimental Autoimmune Encephalomyelitis,” Journal of Neuroinflammation 10 (2013): 49.

[173] D. Antal, Á. Pór, I. Kovács, et al., “PARP2 promotes Inflammation in Psoriasis by Modulating Estradiol Biosynthesis in Keratinocytes,” Journal of Molecular Medicine 101, no. 8 (2023): 987-999.

[174] E. Pöstyéni, R. Gábriel, A. Kovács-Valasek, “Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors in Diabetic Retinopathy: An Attractive but Elusive Choice for Drug Development,” Pharmaceutics 16, no. 10 (2024): 1320.

[175] J. Sun, L. Chen, R. Chen, Q. Lou, H. Wang, “Poly(ADP-ribose) Polymerase-1: An Update on Its Role in Diabetic Retinopathy,” Discovery Medicine 32, no. 165 (2021): 13-22.

[176] Y. Wu, Y. Chen, Q. Wu, L. Jia, X. Du, “Minocycline Inhibits PARP‑1 Expression and Decreases Apoptosis in Diabetic Retinopathy,” Molecular Medicine Reports 12, no. 4 (2015): 4887-4894.

[177] Y. Zhang and W. Wang, “Bidirectional Regulation Role of PARP-1 in High Glucose-induced Endothelial Injury,” Experimental Cell Research 421, no. 2 (2022): 113400.

[178] J. Xiang, X. L. Qi, K. Cao, et al., “Exposure to Fluoride Exacerbates the Cognitive Deficit of Diabetic Patients Living in Areas With Endemic Fluorosis, as Well as of Rats With Type 2 Diabetes Induced by Streptozotocin via a Mechanism That May Involve Excessive Activation of the Poly(ADP ribose) Polymerase-1/P53 Pathway,” The Science of the Total Environment 912 (2024): 169512.

[179] N. Zhang, Y. Zhang, W. Miao, et al., “An Unexpected Role for BAG3 in Regulating PARP1 Ubiquitination in Oxidative Stress-related Endothelial Damage,” Redox Biology 50 (2022): 102238.

[180] D. H. Kwon, S. Shin, J. Ryu, et al., “Neddylation of PARP-1 Is Mediated by CBLB and Regulates Its Activity in Vascular Calcification,” Atherosclerosis 379 (2023): S30.

[181] Y. Yang, X. Li, S. Xiao, et al., “PARylation of POLG Mediated by PARP1 Accelerates Ferroptosis-Induced Vascular Calcification via Activating Adora2a/Rap1 Signaling,” Arteriosclerosis, Thrombosis, and Vascular Biology 45, no. 7 (2025): 1175-1191.

[182] D.-H. Kwon, S. Shin, Y. S. Nam, et al., “CBL-b E3 Ligase-mediated Neddylation and Activation of PARP-1 Induce Vascular Calcification,” Experimental & Molecular Medicine 56, no. 10 (2024): 2246-2259.

[183] B. Maru, A. Messikommer, L. Huang, et al., “PARP-1 Improves Leukemia Outcomes by Inducing Parthanatos During Chemotherapy,” Cell Reports Medicine 4, no. 9 (2023): 101191.

[184] L. Tang, Y. Shi, Q. Liao, et al., “Reversing Metabolic Reprogramming by CPT1 Inhibition With etomoxir Promotes Cardiomyocyte Proliferation and Heart Regeneration via DUSP1 ADP-ribosylation-mediated p38 MAPK Phosphorylation,” Acta Pharmaceutica Sinica B 15, no. 1 (2025): 256-277.

[185] C. Huang, X. Zhang, S. Wang, et al., “PARP-2 Mediates Cardiomyocyte Aging and Damage Induced by Doxorubicin Through SIRT1 Inhibition,” Apoptosis 29, no. 5-6 (2024): 816-834.

[186] E. C. Chan, A. J. Ablooglu, C. C. Ghosh, et al., “PARP15 Is a Susceptibility Locus for Clarkson Disease (Monoclonal Gammopathy-Associated Systemic Capillary Leak Syndrome),” Arteriosclerosis, Thrombosis, and Vascular Biology 44, no. 12 (2024): 2628-2646.

[187] S. Hou, J. Zhang, X. Jiang, et al., “PARP5A and RNF146 Phase Separation Restrains RIPK1-dependent Necroptosis,” Molecular Cell 84, no. 5 (2024): 938-954. e8.

[188] H. Kumar, T. Kawai, S. Akira, “Pathogen Recognition by the Innate Immune System,” International Reviews of Immunology 30, no. 1 (2011): 16-34.

[189] S. R. Paludan, A. G. Bowie, K. A. Horan, K. A. Fitzgerald, “Recognition of Herpesviruses by the Innate Immune System,” Nature Reviews Immunology 11, no. 2 (2011): 143-154.

[190] H. Papp, E. Tóth, J. Bóvári-Biri, et al., “The PARP Inhibitor Rucaparib Blocks SARS-CoV-2 Virus Binding to Cells and the Immune Reaction in Models of COVID-19,” British Journal of Pharmacology 181, no. 23 (2024): 4782-4803.

[191] D. I. Lampropoulou, V. M. Bala, E. Zerva, et al., “The Potential Role of the Combined PARP-1 and VEGF Inhibition in Severe SARS-CoV-2 (COVID-19) Infection,” Journal of Infection in Developing Countries 16, no. 1 (2022): 101-111.

[192] C. M. Kerr, S. Parthasarathy, N. Schwarting, et al., “PARP12 is Required to Repress the Replication of a Mac1 Mutant Coronavirus in a Cell and Tissue Specific Manner,” Biorxiv: the Preprint Server for Biology (2023), https://doi.org/10.1101/2023.06.16.545351.

[193] J. Mateo, C. J. Lord, V. Serra, et al., “A Decade of Clinical Development of PARP Inhibitors in Perspective,” Annals of Oncology 30, no. 9 (2019): 1437-1447.

[194] Y. Luo, Y. Xia, D. Liu, et al., “Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-recombination-deficient Tumors,” Cell 187, no. 18 (2024): 4905-4925. e24.

[195] J. Bhin, M. Paes Dias, E. Gogola, et al., “Multi-omics Analysis Reveals Distinct Non-reversion Mechanisms of PARPi Resistance in BRCA1- versus BRCA2-deficient Mammary Tumors,” Cell Reports 42, no. 5 (2023): 112538.

[196] P. DiSilvestro, S. Banerjee, N. Colombo, et al., “Overall Survival with Maintenance Olaparib at a 7-Year Follow-Up in Patients with Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial,” Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 41, no. 3 (2023): 609-617.

[197] C. E. Geyer, J. E. Garber, R. D. Gelber, et al., “Overall Survival in the OlympiA Phase III Trial of Adjuvant Olaparib in Patients With Germline Pathogenic Variants in BRCA1/2 and High-risk, Early Breast Cancer,” Annals of Oncology 33, no. 12 (2022): 1250-1268.

[198] J. Mateo, J. S. de Bono, K. Fizazi, et al., “Olaparib for the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial,” Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 42, no. 5 (2024): 571-583.

[199] B. J. Monk, M. P. Barretina-Ginesta, B. Pothuri, et al., “Niraparib First-line Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer: Final Overall Survival Results From the PRIMA/ENGOT-OV26/GOG-3012 Trial,” Annals of Oncology 35, no. 11 (2024): 981-992.

[200] B. J. Monk, C. Parkinson, M. C. Lim, et al., “A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients with Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45),” Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 40, no. 34 (2022): 3952-3964.

[201] W. Abida, D. Campbell, A. Patnaik, et al., “Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated With a DNA Damage Repair Gene Alteration: Final Results From the Phase 2 TRITON2 Study,” European Urology 84, no. 3 (2023): 321-330.

[202] K. Fizazi, A. A. Azad, N. Matsubara, et al., “First-line Talazoparib With Enzalutamide in HRR-deficient Metastatic Castration-resistant Prostate Cancer: The Phase 3 TALAPRO-2 Trial,” Nature Medicine 30, no. 1 (2024): 257-264.

[203] J. J. Gruber, A. Afghahi, K. Timms, et al., “A Phase II Study of talazoparib Monotherapy in Patients With Wild-type BRCA1 and BRCA2 With a Mutation in Other Homologous Recombination Genes,” Nat Cancer 3, no. 10 (2022): 1181-1191.

[204] N. Li, Y. Zhang, J. Wang, et al., “Fuzuloparib Maintenance Therapy in Patients with Platinum-Sensitive, Recurrent Ovarian Carcinoma (FZOCUS-2): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial,” Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 40, no. 22 (2022): 2436-2446.

[205] T. Zhang, B. Wang, Y. Wei, et al., “Neoadjuvant Fuzuloparib Combined With Abiraterone for Localized High-risk Prostate Cancer (FAST-PC): A Single-arm Phase 2 Study,” Cell Reports Medicine 6, no. 3 (2025): 102018.

[206] J. Nie, H. Wu, L. Sun, Y. Ding, Y. Luan, J. Wu, “Cost-effectiveness of fuzuloparib Compared to Routine Surveillance, Niraparib and Olaparib for Maintenance Treatment of Patients With Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Carcinoma in China,” Frontiers in Pharmacology 13 (2022): 987337.

[207] E. Rodler, P. Sharma, W. E. Barlow, et al., “Cisplatin With Veliparib or Placebo in Metastatic Triple-negative Breast Cancer and BRCA Mutation-associated Breast Cancer (S1416): A Randomised, Double-blind, Placebo-controlled, Phase 2 Trial,” The Lancet Oncology 24, no. 2 (2023): 162-174.

[208] C. E. Geyer, W. M. Sikov, J. Huober, et al., “Long-term Efficacy and Safety of Addition of Carboplatin With or Without Veliparib to Standard Neoadjuvant Chemotherapy in Triple-negative Breast Cancer: 4-year Follow-up Data From BrighTNess, a Randomized Phase III Trial,” Annals of Oncology 33, no. 4 (2022): 384-394.

[209] J. N. Sarkaria, S. H. Kizilbash, C. Giannini, “Veliparib plus Temozolomide for MGMT-Methylated Glioblastoma-Reply,” JAMA Oncology 11, no. 5 (2025): 569-570.

[210] F. Kang, M. Niu, Z. Zhou, et al., “Spatiotemporal Concurrent PARP Inhibitor Sensitization Based on Radiation-Responsive Nanovesicles for Lung Cancer Chemoradiotherapy,” Advanced Healthcare Materials 13, no. 28 (2024): e2400908.

[211] X. Wu, J. Zhu, R. Yin, et al., “Niraparib Maintenance Therapy Using an Individualised Starting Dose in Patients With Platinum-sensitive Recurrent Ovarian Cancer (NORA): Final Overall Survival Analysis of a Phase 3 Randomised, Placebo-controlled Trial,” EClinicalMedicine 72 (2024): 102629.

[212] X. H. Wu, J. Q. Zhu, R. T. Yin, et al., “Niraparib Maintenance Therapy in Patients With Platinum-sensitive Recurrent Ovarian Cancer Using an Individualized Starting Dose (NORA): A Randomized, Double-blind, Placebo-controlled Phase III Trial ☆,” Annals of Oncology : Official Journal of the European Society for Medical Oncology 32, no. 4 (2021): 512-521.

[213] N. Matsubara, A. A. Azad, N. Agarwal, et al., “First-line Talazoparib plus Enzalutamide versus Placebo plus Enzalutamide for Metastatic Castration-resistant Prostate Cancer: Patient-reported Outcomes From the Randomised, Double-blind, Placebo-controlled, Phase 3 TALAPRO-2 Trial,” The Lancet Oncology 26, no. 4 (2025): 470-480.

[214] B. L. Heiss, E. Chang, X. Gao, et al., “US Food and Drug Administration Approval Summary: Talazoparib in Combination with Enzalutamide for Treatment of Patients with Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer,” Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 42, no. 15 (2024): 1851-1860.

[215] N. Agarwal, A. A. Azad, J. Carles, et al., “Talazoparib plus Enzalutamide in Men With First-line Metastatic Castration-resistant Prostate Cancer (TALAPRO-2): A Randomised, Placebo-controlled, Phase 3 Trial,” Lancet (London, England) 402, no. 10398 (2023): 291-303.

[216] M. Kolesnichenko, C. Scheidereit, “Synthetic Lethality by PARP Inhibitors: New Mechanism Uncovered Based on Unresolved Transcription-replication Conflicts,” Signal Transduction and Targeted Therapy 9, no. 1 (2024): 179.

[217] M. Petropoulos, A. Karamichali, G. G. Rossetti, et al., “Transcription-replication Conflicts Underlie Sensitivity to PARP Inhibitors,” Nature 628, no. 8007 (2024): 433-441.

[218] Y. Pommier, M. J. O'Connor, J. de Bono, “Laying a Trap to Kill Cancer Cells: PARP Inhibitors and Their Mechanisms of Action,” Science Translational Medicine 8, no. 362 (2016): 362ps17.

[219] P. Michalis, K. Angeliki, G. R. Giacomo, et al., “Transcription-replication Conflicts Underlie Sensitivity to PARP Inhibitors,” Nature 628, no. 8007 (2024): 433-441.

[220] D. Dibitetto, C. A. Widmer, S. Rottenberg, “PARPi, BRCA, and Gaps: Controversies and Future Research,” Trends in Cancer 10, no. 9 (2024): 857-869.

[221] Y. Xue, T. Yin, S. Yuan, et al., “CYP1B1 promotes PARPi-resistance via Histone H1.4 Interaction and Increased Chromatin Accessibility in Ovarian Cancer,” Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy 77 (2024): 101151.

[222] M. Xiao, R. Tang, H. Pan, et al., “TPX2 serves as a Novel Target for Expanding the Utility of PARPi in Pancreatic Cancer Through Conferring Synthetic Lethality,” Gut 74, no. 3 (2025): 410-423.

[223] W. LM, W. P, C. XM, et al., “Thioparib Inhibits Homologous Recombination Repair, Activates the Type I IFN Response, and Overcomes Olaparib Resistance,” EMBO Molecular Medicine 15, no. 3 (2023): e16235.

[224] Z. Tang, P. G. Pilié, C. Geng, et al., “ATR Inhibition Induces CDK1-SPOP Signaling and Enhances Anti-PD-L1 Cytotoxicity in Prostate Cancer,” Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 27, no. 17 (2021): 4898-4909.

[225] W. Wu, W. Wu, X. Xie, et al., “DNMT1 is Required for Efficient DSB Repair and Maintenance of Replication Fork Stability, and Its Loss Reverses Resistance to PARP Inhibitors in Cancer Cells,” Oncogene 44, no. 27 (2025): 2283-2302.

[226] C. Cao, J. Yang, Y. Chen, et al., “Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers,” Journal of Medicinal Chemistry 63, no. 19 (2020): 11012-11033.

[227] E. Pujade-Lauraine, F. Selle, G. Scambia, et al., “Maintenance Olaparib Rechallenge in Patients With Platinum-sensitive Relapsed Ovarian Cancer Previously Treated With a PARP Inhibitor (OReO/ENGOT-ov38): A Phase IIIb Trial,” Annals of Oncology 34 (2023): 1152-1164.

[228] D. Bondar, Y. Karpichev, “Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions,” Biomolecules 14, no. 10 (2024): 1269.

[229] M. Niepel, M. M. Vasbinder, J. P. Molina, et al. The PARP14 inhibitor RBN-3143 suppresses lung inflammation in preclinical models. 2022.

[230] V. C. Ribeiro, L. C. Russo, N. C. Hoch, “PARP14 is Regulated by the PARP9/DTX3L Complex and Promotes Interferon γ-induced ADP-ribosylation,” The EMBO Journal 43, no. 14 (2024): 2908-2928.

[231] L. C. Russo, R. Tomasin, I. A. Matos, et al., “The SARS-CoV-2 Nsp3 Macrodomain Reverses PARP9/DTX3L-dependent ADP-ribosylation Induced by Interferon Signaling,” The Journal of Biological Chemistry 297, no. 3 (2021): 101041.

[232] C. A. Eide, M. S. Zabriskie, S. L. Savage Stevens, et al., “Combining the Allosteric Inhibitor Asciminib With Ponatinib Suppresses Emergence of and Restores Efficacy Against Highly Resistant BCR-ABL1 Mutants,” Cancer Cell 36, no. 4 (2019): 431-443. e5.

[233] M. J. Suskiewicz, F. Zobel, T. E. H. Ogden, et al., “HPF1 completes the PARP Active Site for DNA Damage-induced ADP-ribosylation,” Nature 579, no. 7800 (2020): 598-602.

[234] J. Rudolph, G. Roberts, K. Luger, “Histone Parylation Factor 1 Contributes to the Inhibition of PARP1 by Cancer Drugs,” Nature Communications 12, no. 1 (2021): 736.

[235] Y. Wu, M. Wu, X. Zheng, et al., “Discovery of a Potent and Selective PARP1 Degrader Promoting Cell Cycle Arrest via Intercepting CDC25C-CDK1 Axis for Treating Triple-negative Breast Cancer,” Bioorganic Chemistry 142 (2024): 106952.

[236] A. Bardia, S. Sun, N. Thimmiah, et al., “Antibody-Drug Conjugate Sacituzumab Govitecan Enables a Sequential TOP1/PARP Inhibitor Therapy Strategy in Patients With Breast Cancer. Clinical Cancer Research : An Official Journal of the,” American Association for Cancer Research 30, no. 14 (2024): 2917-2924.

[237] L. Abujamous, A. Soltani, H. Al-Thawadi, A. Agouni, “Advances in Nanotechnology-enabled Drug Delivery for Combining PARP Inhibitors and Immunotherapy in Advanced Ovarian Cancer,” Biomolecules & Biomedicine 24, no. 2 (2024): 230-237.

[238] P. Gralewska, A. Gajek, A. Marczak, A. Rogalska, “Targeted Nanocarrier-Based Drug Delivery Strategies for Improving the Therapeutic Efficacy of PARP Inhibitors Against Ovarian Cancer,” International Journal of Molecular Sciences 25, no. 15 (2024): 8304.

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