Novel modulators of poly(ADP-ribose) polymerase - PubMed (original) (raw)

Novel modulators of poly(ADP-ribose) polymerase

Csaba Szabo et al. Trends Pharmacol Sci. 2006 Dec.

Abstract

The nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 has an important role in regulating cell death and cellular responses to DNA repair. Pharmacological inhibitors of PARP have entered clinical testing as cytoprotective agents in cardiovascular diseases and as adjunct antitumor therapeutics. Initially, it was assumed that the regulation of PARP occurs primarily at the level of DNA breakage: recognition of DNA breaks was considered to be the primary regulator (activator) or the catalytic activity of PARP. Recent studies have provided evidence that PARP-1 activity can also be modulated by several endogenous factors, including various kinases, purines and caffeine metabolites. There is a gender difference in the contribution of PARP-1 to stroke and inflammatory responses, which is due, at least in part, to endogenous estrogen levels. Several tetracycline antibiotics are also potent PARP-1 inhibitors. In this article, we present an overview of novel PARP-1 modulators.

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Figures

Figure 1

Figure 1

Endogenous and exogenous regulators and modulators of PARP-1 activity. Endogenous factors can affect PARP-1 activity either by forming a complex with PARP-1 or by inhibiting the binding of NAD+ to the active site of the enzyme. The former might include estrogen (E) and thyroid hormones (T), and the latter might include nicotinamide (NA), NAD+ metabolites, caffeine metabolites and vitamin D. PARP-1 activity can also be modulated through phosphorylation by kinases (e.g. MAPK and CaMKIIδ, and PKC), by Sirt1 and through binding to KIF4. PARP can also modulate kinase (e.g. AKT and JNK) activity. Exogenous factors such as caffeine and its endogenously formed metabolites, theophylline and tetracycline antibiotics might also modulate PARP activity. Overall, PARP seems to be subject to multiple lines of endogenous regulators, and it is conceivable that the processes regulated by PARP (e.g. DNA repair and cellular NAD homeostasis) are under similarly dynamic control by a multitude of factors and influences. Abbreviations: ER, estrogen receptor; TR, thyroid hormone receptor.

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