Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes

Abstract

Poly(ADP-ribose) polymerases (PARPs) are NAD(+) dependent enzymes that were identified as DNA repair proteins, however, today it seems clear that PARPs are responsible for a plethora of biological functions. Sirtuins (SIRTs) are NAD(+)-dependent deacetylase enzymes involved in the same biological processes as PARPs raising the question whether PARP and SIRT enzymes may interact with each other in physiological and pathophysiological conditions. Hereby we review the current understanding of the SIRT-PARP interplay in regard to the biochemical nature of the interaction (competition for the common NAD(+) substrate, mutual posttranslational modifications and direct transcriptional effects) and the physiological or pathophysiological consequences of the interactions (metabolic events, oxidative stress response, genomic stability and aging). Finally, we give an overview of the possibilities of pharmacological intervention to modulate PARP and SIRT enzymes either directly, or through modulating NAD(+) homeostasis.

Keywords: Metabolism; Mitochondria; NAD(+); Oxidative stress; Poly(ADP-ribose) polymerase; Sirtuins SIRT1.

Figure 1. NAD and reactions of NAD⁺

(A) Depiction of the chemical structure of NAD⁺. (B) Transfer of hydride to nicotinamide of NAD⁺ to form NADH. (C) ADP-ribosyltransfer reaction of NAD⁺ to a cellular nucleophile (acetyllysine, aspartate, glutamate, protein, etc).

Figure 2. NAD⁺ biosynthetic pathways in mammals

Naming derives from mammalian abbreviations. NA: nicotinic acid; NR: NAM riboside; NAM: nicotinamide; NAM NMN: NAM mononucleotide; NaMN: nicotinic acid mononucleotide; NaAD: nicotinic acid adenine dinucleotide; QPT: nicotinic acid phosphoribosyl-transferase; NRK: NAM riboside kinase; ART: ADP-ribosyl transferase; PARP: poly-ADP-polymerase; Nampt: NAM phosphoribosyltransferase; PNP: purine nucleoside phosphorylase; NMNAT: NMN/NaMN adenylyltransferase.

Figure 3. An overview of the deacetylation reactions catalyzed by SIRT1 and mono/poly(ADP-ribosyl)ation reactions catalyzed by PARPs

Figure 4. The molecular level interactions between SIRT1 PARP-1 and -2 under oxidative stress conditions

The pathways enhancing oxidative stress-mediated tissue damage are in red, in turn, protective pathways are in green. Oxidative stress induces PARP-1 that through the depletion of NAD⁺ pools inhibits SIRT1. That pathway seems to participate in the tissue damage inflicted by PARP activation. On the contrary, SIRT1 activation by pharmacological agents (e.g. resveratrol, fistein) or by induction of its expression (e.g. PARP-2 ablation) leads to SIRT1-mediated deacetylation and inactivation of PARP-1 that seems a crucial pathway in the cytoprotective action of SIRT1 activation.

Figure 5. Compounds that modulate NAD⁺ concentrations or modulate GPR109A

Figure 6. Examples of compounds that (A) activate and (B) inhibit SIRT1 or other sirtuins

Figure 7. Compounds that inhibit PARPs as discussed in the text

Figure 8. Physiological and pathophysiological processes modulating NAD⁺ levels

Physiolgical and pathological processes (in blue boxes) that enhance NAD⁺ content, or availability are marked by green arrow, while those ones that lead to NAD⁺ degradation are in red.