Molecular aspects of medicine
-
Poly(ADP-ribosyl)ation (PARylation) is a posttranslational protein modification (PTM) catalyzed by members of the poly(ADP-ribose) polymerase (PARP) enzyme family. PARPs use NAD(+) as substrate and upon cleaving off nicotinamide they transfer the ADP-ribosyl moiety covalently to suitable acceptor proteins and elongate the chain by adding further ADP-ribose units to create a branched polymer, termed poly(ADP-ribose) (PAR), which is rapidly degraded by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3). ⋯ These paradigm shifts include but are not limited to (1) a single PARP enzyme expanding to a PARP family; (2) DNA-break dependent activation extended to several other DNA dependent and independent PARP-activation mechanisms; (3) one molecular mechanism (covalent PARylation of target proteins) underlying the biological effect of PARPs is now complemented by several other mechanisms such as protein-protein interactions, PAR signaling, modulation of NAD(+) pools and (4) one principal biological role in DNA damage sensing expanded to numerous, diverse biological functions identifying PARP-1 as a real moonlighting protein. Here we review the most important paradigm shifts in PARylation research and also highlight some of the many controversial issues (or paradoxes) of the field such as (1) the mostly synergistic and not antagonistic biological effects of PARP-1 and PARG; (2) mitochondrial PARylation and PAR decomposition, (3) the cross-talk between PARylation and signaling pathways (protein kinases, phosphatases, calcium) and the (4) divergent roles of PARP/PARylation in longevity and in age-related diseases.
-
The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination repair (HRR) is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. ⋯ In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.