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

Elie Toledano (1) , Vasily Ogryzko (2) , Antoine Danchin (3) , Daniel Ladant (1) , Undine Mechold (1)

1 Biochimie des Interactions Macromoléculaires / Biochemistry of Macromolecular Interactions
2 IMC (UMR 8126) - Interactions moléculaires et cancer
3 AMAbiotics SAS

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.

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Biochemistry, Molecular Biology

Elie Toledano, Vasily Ogryzko, Antoine Danchin, Daniel Ladant, Undine Mechold. 3'-5' phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo.. Biochemical Journal, 2012, 443 (2), pp.485-90. ⟨10.1042/BJ20111057⟩. ⟨pasteur-01427528⟩