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 ageing). Finally, we give an overview of the possibilities of pharmacological intervention to modulate PARP and SIRT enzymes either directly, or through modulating NAD+ homeostasis.

Poly(ADP-ribose) polymerases as modulators of mitochondrial activity

“…Reduced mitochondrial activity has been associated with several pathologies ranging from neurodegeneration to metabolic diseases [1]. PARPs (see Glossary) are predominantly nuclear enzymes that are involved in cellular stress responses, both as sensors of cellular damage, and as active participants in stress response (e.g., PARP-1 is a DNA damage sensor and a member of the DNA repair machinery) [2]. Although overactivation of some PARP family members (e.g., PARP-1 or PARP-2) was shown to hamper mitochondrial activity in response to oxidative stress and nutrient availability, the actual pathways through which PARPs regulate mitochondrial function are not fully understood.…”

“…proteins or NAD + metabolites (for detailed overviews see [2,4,5]). PARPs are involved in DNA repair processes, transcriptional regulation, cell death in oxidative stress related pathologies, and metabolic and immune regulation [6].…”

“…Despite sequence similarity in the catalytic domains between PAPR family members, only PARP-1, PARP-2, and tankyrases are known to produce long PAR polymers, while other PARP enzymes are defective in elongation or are inactive [3]. Hence, the majority of both basal and stimulated cellular PARP activity is attributed to PARP-1 (85-90%) and PARP-2 (10-15%) [2]. Activation of the nuclear PARP-1, -2, and -3 can be triggered by single or double strand breaks in DNA, frequently induced by oxygen or nitrogen reactive species (ROS, RNS), or abnormal DNA structures [2].…”

“…Activation of the nuclear PARP-1, -2, and -3 can be triggered by single or double strand breaks in DNA, frequently induced by oxygen or nitrogen reactive species (ROS, RNS), or abnormal DNA structures [2]. There is accumulating evidence that alternative pathways of PARP-1/2 activation exist, such as increases in intracellular calcium, kinase cascades (e.g., ERKs), mono-ADP-ribosylation, and acetylation, whereas self-PARylation, phosphorylation by protein kinase C (PKC), or SUMOylation are inhibitory [2,6,8].…”

“…Several PARG isoforms exist, due to alternative splicing, that can be found in most cellular compartments [9]. Besides PARG, ADP-ribosylacceptor hydrolase 3 (ARH3), ADP-ribosyl lyase and macrodomain-containing proteins are also important regulators of cellular PAR levels [2,5,[9][10][11]. ADPR can be further metabolized to AMP by nucleoside diphosphate linked to X (NUDIX) pyrophosphatases [12].…”