An Update on Poly(ADP-ribose) Polymerase I-A Brief Review

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) plays important roles in both DNA repair and transcription, and the interplay of these processes in relation to cellular function and disease states has not been well defined. The tumor-suppressor effects of PARP inhibitors have attracted significant interest in the development of novel cancer therapies. As PARP1 binding motifs may be readily found in promoter elements of DNA repair genes, the expanding role of PARP1 in DNA repair does not have to be independent of transcription. The discovery of ADP-ribose binding modules that bind to various forms of mono- and poly-ADP-ribose has provided important insights into how ADP-ribosylation regulates different cellular pathways. Among the four distinct PAR-binding modules discovered so far, it is the macrodomain alone that, in addition to possessing binding activity, in some instances, also supports a catalytic activity toward ADP-ribose derivatives. However, the development of PARP inhibitors as chemopotentiating agents has been limited by an increase in observed toxicity, mainly myelosuppression, necessitating dose reduction of the cytotoxic chemotherapeutic agent and the PARP inhibitor. Hence, it presents an opportunity to rationally develop combinations of PARP inhibitors with new classes of DNA repair inhibitors that are on the horizon and classical cytotoxic agents. Clinical trials of PARP inhibitors are investigating various uses of these approaches in cancer. Recent studies on the clinical significance of PARP1 inhibitors are discussed in this review. These recent research advances will inform the selection of patient populations who can benefit from the PARP inhibitor treatment and the development of effective drug combination strategies.

Design, Synthesis, and Evaluation of [18F]BIBD-300 as a Positron Emission Tomography Tracer for Poly(ADP-Ribose) Polymerase-1

“…In addition to the PARP repair pathway, normal cells can also repair DNA damage through base exception repair (BER), homologous recovery repair (HRR), classical and alternative nonhomologous end joining (NHEJ), nucleotide exception repair (NER), and mismatch repair (MMR). − However, some cancer cells are HRR deficient, which causes them to rely mainly on PARP to repair DNA damage. If PARP is inactivated, these cancer cells are unable to repair damaged DNA and may even die, while normal cells can still tolerate it. ,− PARP-1 is the most important member of the PARP family and plays more than 90% of the functions of the PARP family in cells . Therefore, PARP-1-targeting inhibitors, such as olaparib, rucaparib, niraparib, and talazoparib, have been developed and approved as therapeutic drugs for breast cancer, ovarian cancer, pancreatic cancer, and other tumors. − …”

“…Poly­(ADP-ribose) polymerase (PARP) is a class of ribozymes that are found mainly in eukaryotic cells and are involved in DNA repair, transcription, regulation, and other processes . In addition to the PARP repair pathway, normal cells can also repair DNA damage through base exception repair (BER), homologous recovery repair (HRR), classical and alternative nonhomologous end joining (NHEJ), nucleotide exception repair (NER), and mismatch repair (MMR). − However, some cancer cells are HRR deficient, which causes them to rely mainly on PARP to repair DNA damage.…”

PARP1 Promotes Heart Regeneration and Cardiomyocyte Proliferation

“…Its primary function is to transfer ADP-ribose polymer chains from NAD + to acceptor proteins or PARP1 protein itself, called posttranslational poly(ADP-ribosyl)ation modification [3]. PARP1 participates in a multitude of cellular processes, such as transcriptional activation, cell death, chromatin remodeling, and energy metabolism [4]. Increasing evidence has indicated the involvement of PARP1 in a range of cardiovascular diseases, such as cardiac hypertrophy, arrhythmia, atherosclerosis, hypertension, and vascular calcification [5][6][7][8][9].…”