Review Poly(ADP-ribose) polymerase-1 (PARP-1) and its therapeutic implications Rupinder K. Sodhi, Nirmal Singh ⁎, Amteshwar S. Jaggi Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, Punjab, India abstract article info Article history: Received 5 February 2010 Received in revised form 3 May 2010 Accepted 16 June 2010 Keywords: PARP-1 Apoptosis Necrosis DNA repair PARP inhibitors Poly(ADP-ribose) polymerases (PARPs) are a family of cell signaling enzymes present in eukaryotes, which are involved in the poly(ADP-ribosylation) of DNA binding proteins. While an 18 member superfamily of PARPs has been identified, however PARP-1 the most abundant isoform accounts for more than 90% of its functions. PARP-1 works as DNA damage nick sensor, which uses NAD + to form polymers of ADP-ribose (PAR) and nicotinamide. Three consequences of the activation of PARP-1 are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of proinflammatory genes. Consequently, pharmacological inhibition of PARP has the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications). Through this article we have tried to develop a brief and simplified picture of the principal physiological and pathophysiological roles governed by PARP-1 and its therapeutic implications. © 2010 Elsevier Inc. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 2. PARP-1: the founding member of the PARP family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 3. Physiological roles of PARP-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 3.1. PARP-1 and DNA repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 3.2. PARP-1 and cell death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 3.3. PARP and proinflammatory signal transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4. Modulators of PARP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 4.1. Classical PARP inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 4.2. Newer PARP inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 4.3. Zinc finger PARP inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 5. PARP-1 and pathological disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 5.1. PARP-1 in neuronal injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 5.2. PARP-1 in inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 5.3. PARP-1 in diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 5.4. PARP-1 in HIV infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 5.5. PARP-1 in Parkinsonism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 5.6. PARP-1 in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 5.7. PARP-1 in aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 5.8. PARP-1 in ischemia–reperfusion injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Vascular Pharmacology 53 (2010) 77–87 ⁎ Corresponding author. Tel.: +91 175 3046255, +919815129884 (mobile); fax: +91 981 5129884. E-mail address: nirmal_puru@rediffmail.com (N. Singh). 1537-1891/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2010.06.003 Contents lists available at ScienceDirect Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph