3′-5′ Phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo

Author:

Toledano Elie1,Ogryzko Vasily2,Danchin Antoine3,Ladant Daniel1,Mechold Undine1

Affiliation:

1. Institut Pasteur, CNRS UMR 3528, Unité de Biochimie des Interactions macromoléculaires, Département de Biologie Strucurale et Chimie, 25–28 rue du Docteur Roux, 75724 Paris cedex 15, France

2. Institut Gustave Roussy, UMR 8126, Unité d'Interactions Moléculaires et Cancer, 94805 Villejuif, France

3. AMAbiotics SAS, 5 rue Henri Desbruères, 91030 Evry Cedex, France

Abstract

pAp (3′-5′ phosphoadenosine phosphate) is a by-product of sulfur and lipid metabolism and has been shown to have strong inhibitory properties on RNA catabolism. In the present paper we report a new target of pAp, PARP-1 [poly(ADP-ribose) polymerase 1], a key enzyme in the detection of DNA single-strand breaks. We show that pAp can interact with PARP-1 and inhibit its poly(ADP-ribosyl)ation activity. In vitro, inhibition of PARP-1 was detectable at micromolar concentrations of pAp and altered both PARP-1 automodification and heteromodification of histones. Analysis of the kinetic parameters revealed that pAp acted as a mixed inhibitor that modulated both the Km and the Vmax of PARP-1. In addition, we showed that upon treatment with lithium, a very potent inhibitor of the enzyme responsible for pAp recycling, HeLa cells exhibited a reduced level of poly(ADP-ribosyl)ation in response to oxidative stress. From these results, we propose that pAp might be a physiological regulator of PARP-1 activity.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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