This subfamily of four enzymes (the PARylating PARPs) catalyse the addition of poly-ADP-ribose chains as post-translational protein modifications . The best characterised members are the nuclear enzymes PARP1, PARP2 and the tankyrases (TNKSs). PARPs 1 and 2 appear to function by binding to single strand breaks in DNA, allowing the recruitment of repair enzymes by the synthesis of NAD-derived ADP-ribose polymers, that are subsequently degraded by a glycohydrolase (PARG, Q86W56). The most well defined function of the tankyrases (TNKSs) is their regulatory action on Wnt/β-catenin signalling [3]. PARPs 1 and 2 are targets of PARP inhibitor class anti-cancer drugs which are designed to disrupt the DNA damage response pathways to induce cancer cell death.

* Key recommended reading is highlighted with an asterisk

Berger NA, Besson VC, Boulares AH, Bürkle A, Chiarugi A, Clark RS, Curtin NJ, Cuzzocrea S, Dawson TM, Dawson VL et al.. (2018) Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases. Br J Pharmacol, 175 (2): 192-222. [PMID:28213892]

Bürkle A, Virág L. (2013) Poly(ADP-ribose): PARadigms and PARadoxes. Mol Aspects Med, 34 (6): 1046-65. [PMID:23290998]

Cavone L, Chiarugi A. (2012) Targeting poly(ADP-ribose) polymerase-1 as a promising approach for immunomodulation in multiple sclerosis?. Trends Mol Med, 18 (2): 92-100. [PMID:22078487]

* Curtin NJ, Szabo C. (2020) Poly(ADP-ribose) polymerase inhibition: past, present and future. Nat Rev Drug Discov, 19 (10): 711-736. [PMID:32884152]

De Vos M, Schreiber V, Dantzer F. (2012) The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochem Pharmacol, 84 (2): 137-46. [PMID:22469522]

Ekblad T, Camaioni E, Schüler H, Macchiarulo A. (2013) PARP inhibitors: polypharmacology versus selective inhibition. FEBS J, 280 (15): 3563-75. [PMID:23601167]

Faraoni I, Giansanti M, Voso MT, Lo-Coco F, Graziani G. (2019) Targeting ADP-ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders. Biochem Pharmacol, 167: 133-148. [PMID:31028744]

Gibson BA, Kraus WL. (2012) New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol, 13 (7): 411-24. [PMID:22713970]

* Grignani G, Merlini A, Sangiolo D, D'Ambrosio L, Pignochino Y. (2020) Delving into PARP inhibition from bench to bedside and back. Pharmacol Ther, 206: 107446. [PMID:31756364]

* Lal S, Snape TJ. (2021) A therapeutic update on PARP inhibitors: implications in the treatment of glioma. Drug Discov Today, 26 (2): 532-541. [PMID:33157194]

* Leung AKL. (2020) Poly(ADP-ribose): A Dynamic Trigger for Biomolecular Condensate Formation. Trends Cell Biol, 30 (5): 370-383. [PMID:32302549]

Lord CJ, Ashworth A. (2012) The DNA damage response and cancer therapy. Nature, 481 (7381): 287-94. [PMID:22258607]

Lupo B, Trusolino L. (2014) Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited. Biochim Biophys Acta, 1846 (1): 201-15. [PMID:25026313]

Michels J, Obrist F, Castedo M, Vitale I, Kroemer G. (2014) PARP and other prospective targets for poisoning cancer cell metabolism. Biochem Pharmacol, 92 (1): 164-71. [PMID:25199458]

* Pandey N, Black BE. (2021) Rapid Detection and Signaling of DNA Damage by PARP-1. Trends Biochem Sci, 46 (9): 744-757. [PMID:33674152]

Pines A, Mullenders LH, van Attikum H, Luijsterburg MS. (2013) Touching base with PARPs: moonlighting in the repair of UV lesions and double-strand breaks. Trends Biochem Sci, 38 (6): 321-30. [PMID:23562323]

* Rao PD, Sankrityayan H, Srivastava A, Kulkarni YA, Mulay SR, Gaikwad AB. (2020) 'PARP'ing fibrosis: repurposing poly (ADP ribose) polymerase (PARP) inhibitors. Drug Discov Today, 25 (7): 1253-1261. [PMID:32371137]

Riffell JL, Lord CJ, Ashworth A. (2012) Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat Rev Drug Discov, 11 (12): 923-36. [PMID:23197039]

Sonnenblick A, de Azambuja E, Azim Jr HA, Piccart M. (2015) An update on PARP inhibitors--moving to the adjuvant setting. Nat Rev Clin Oncol, 12 (1): 27-41. [PMID:25286972]

Szántó M, Brunyánszki A, Kiss B, Nagy L, Gergely P, Virág L, Bai P. (2012) Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein. Cell Mol Life Sci, 69 (24): 4079-92. [PMID:22581363]

Zeniou M, Nguekeu-Zebaze L, Dantzer F. (2019) Therapeutic considerations of PARP in stem cell biology: Relevance in cancer and beyond. Biochem Pharmacol, 167: 107-115. [PMID:31202733]

1. Groelly FJ, Fawkes M, Dagg RA, Blackford AN, Tarsounas M. (2023) Targeting DNA damage response pathways in cancer. Nat Rev Cancer, 23 (2): 78-94. [PMID:36471053]

2. Lau T, Chan E, Callow M, Waaler J, Boggs J, Blake RA, Magnuson S, Sambrone A, Schutten M, Firestein R et al.. (2013) A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res, 73 (10): 3132-44. [PMID:23539443]

3. Mariotti L, Pollock K, Guettler S. (2017) Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding. Br J Pharmacol, 174 (24): 4611-4636. [PMID:28910490]

4. Mizutani A, Yashiroda Y, Muramatsu Y, Yoshida H, Chikada T, Tsumura T, Okue M, Shirai F, Fukami T, Yoshida M et al.. (2018) RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model. Cancer Sci, 109 (12): 4003-4014. [PMID:30238564]

5. Mosca L, Rotili D, Tempera I, Masci A, Fontana M, Chiaraluce R, Mastromarino P, d'Erme M, Mai A. (2011) Biological effects of MC2050, a quinazoline-based PARP-1 inhibitor, in human neuroblastoma and EBV-positive Burkitt's lymphoma cells. ChemMedChem, 6 (4): 606-11. [PMID:21365766]

6. Thorvaldsen TE. (2017) Targeting Tankyrase to Fight WNT-dependent Tumours. Basic Clin Pharmacol Toxicol, 121 (2): 81-88. [PMID:28371398]

7. Tomassi S, Pfahler J, Mautone N, Rovere A, Esposito C, Passeri D, Pellicciari R, Novellino E, Pannek M, Steegborn C et al.. (2020) From PARP1 to TNKS2 Inhibition: A Structure-Based Approach. ACS Med Chem Lett, [Articles ASAP]. DOI: 10.1021/acsmedchemlett.9b00654