Control of AIF-mediated Cell Death by the Functional Interplay of SIRT1 and PARP-1 in Response to DNA Damage

Abstract

Cell survival after genotoxic stress is determined by a counterbalance of pro- and anti-death factors. Sirtuins (SIRTs) are deacetylases that promote cell survival whereas poly(ADP-ribose) polymerases (PARPs) can act both as survival and death inducing factor and the two protein families are strictly dependent on NAD(+) for their activities. Here we report that SIRT1 modulates PARP-1 activity upon DNA damage. Activation of SIRT1 by resveratrol leads to reduced PARP-1 activity and there is a drastic increase in PAR synthesis in sirt1-null cells. The unbalanced regulation of PARP-1 in the absence of SIRT1 results in AIF (apoptosis inducing factor)-mediated cell death. Our findings establish a functional link between the two NAD+-dependent enzyme systems and provide a physiological interpretation for the mechanism of death in cells lacking SIRT1.

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…However, both enzymes are able to block each other's activity by releasing the inhibitory by-product nicotinamide [103]. SIRT1 has also been able to mitigate the rapid PARP-1 activation in oxidative (H 2 O 2 -induced) stress while SIRT1 knock-out has led to enhanced apoptotic signalling and cell loss in these conditions [103].…”

“…However, both enzymes are able to block each other's activity by releasing the inhibitory by-product nicotinamide [103]. SIRT1 has also been able to mitigate the rapid PARP-1 activation in oxidative (H 2 O 2 -induced) stress while SIRT1 knock-out has led to enhanced apoptotic signalling and cell loss in these conditions [103]. The results obtained by Rajamohan suggest that depending on the conditions the difference in K M could be negligible: the value for PARP-1 activated by pERK or the histone acetyltransferase PCAF (p300/CBP-associated factor) is just 10% to 20% lower than that of SIRT1 [163].…”

Novel modulators of poly(ADP-ribose) polymerase

“…Similarly, calmodulin-dependent protein kinase (CaMK)IIδ might also activate PARP-1 by phosphorylation [16], and PARP can modulate AKT kinase (protein kinase B) [17] and JNK [18] kinase activities. Importantly, recent studies have identified the kinesin superfamily protein (KIF)4 [19], and sirtuin or silent mating-type information regulation 2 homolog (Sirt1) [20] as endogenous inhibitors of PARP-1.…”

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

“…This protective response is characterized by the transfer of successive units of the ADP-ribose moiety (up to 200 units) from NAD + to other proteins, compromising therefore both energy production (slowing the rate of glycolysis, electron transport and ATP formation) and activity of other NAD + -dependent enzymes through NAD + depletion. 6,7 Moreover, PARP1-synthesized PAR polymers can be degraded into free oligomers, known to translocate to the mitochondria where they can trigger the release of AIF from mitochondria to the nucleus. [8][9][10][11] The precise molecular steps linking PARP1 activation to this form of stress-induced cell death, termed parthanatos, have not been fully elucidated, and probably depend on the particular metabolic status of the cell examined (i.e., anerobic glycolysis in most in vitro cell lines versus oxidative metabolism of neuronal cells, see Welsby et al 12 for review).…”