Predicted Role of NAD Utilization in the Control of Circadian Rhythms during DNA Damage Response

Abstract

The circadian clock is a set of regulatory steps that oscillate with a period of approximately 24 hours influencing many biological processes. These oscillations are robust to external stresses, and in the case of genotoxic stress (i.e. DNA damage), the circadian clock responds through phase shifting with primarily phase advancements. The effect of DNA damage on the circadian clock and the mechanism through which this effect operates remains to be thoroughly investigated. Here we build an in silico model to examine damage-induced circadian phase shifts by investigating a possible mechanism linking circadian rhythms to metabolism. The proposed model involves two DNA damage response proteins, SIRT1 and PARP1, that are each consumers of nicotinamide adenine dinucleotide (NAD), a metabolite involved in oxidation-reduction reactions and in ATP synthesis. This model builds on two key findings: 1) that SIRT1 (a protein deacetylase) is involved in both the positive (i.e. transcriptional activation) and negative (i.e. transcriptional repression) arms of the circadian regulation and 2) that PARP1 is a major consumer of NAD during the DNA damage response. In our simulations, we observe that increased PARP1 activity may be able to trigger SIRT1-induced circadian phase advancements by decreasing SIRT1 activity through competition for NAD supplies. We show how this competitive inhibition may operate through protein acetylation in conjunction with phosphorylation, consistent with reported observations. These findings suggest a possible mechanism through which multiple perturbations, each dominant during different points of the circadian cycle, may result in the phase advancement of the circadian clock seen during DNA damage.

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“… 236 The circadian control of intracellular NAD + levels by the clock is attributed to the oscillation expression of NAMPT, a rate-limiting enzyme in the salvage of NAD + with a 24-hour rhythm. 36 , 38 , 237 – 239 The E-boxes in the promoter of Nampt gene allow the direct transcriptional control by the CLOCK: BMAL1 chromatin complex. 240 Furthermore, the expression of enzymes in the NAD + salvage pathway, including Nmrk1, Nampt, and Nadk, has circadian oscillation patterns in WT and Liver-RE mice that exclusively express BMAL1 in the liver, suggesting the circadian clock might reprogram NAD + salvage synthesis to maintain the fluctuation of NAD + .…”

Cellular Timekeeping: It’s Redox o’Clock

“…This is supported by the fact that deletion or pharmacological inhibition of PARP-1 results in significantly elevated NAD þ levels and increased SIRT1 activity, indicating that the enzyme is a major NAD þ consumer and in direct competition with the SIRTs for NAD þ availability (Bai et al 2011). In fact, a recent study used computational simulations to show that increased PARP-1 activity in response to DNA damage might be able to induce SIRT1-dependent clock phase shifts because of competition for limited NAD þ supplies (Luna et al 2015).…”

“…As described earlier, another potential way in which oxidative stress might impinge on the molecular clockwork is through the activation of PARP-1 by oxidation-induced DNA damage (Luna et al 2015). Under such conditions, PARP-1 is expected to consume relatively higher amounts of NAD þ and thus limit the availability of the cofactor for the SIRT deacetylase, which would, in turn, affect clock function.…”

Resveratrol: brain effects on SIRT1, GPR50 and photoperiodic signaling

“…While light is the dominant timing cue for melatonin circadian rhythm and for the entrainment of the SCN oscillator in the anterior hypothalamus, our results suggest that resveratrol consumption can also affect the activity of transmembrane receptor-dependent melatonin signaling via SIRT1 activity. As noted in the introductory paragraphs, SIRT1 is involved in the transcriptional activation of circadian rhythms, particularly diurnal rhythms associated with food intake and glucose metabolism (Mattson et al, 2014 ; Luna et al, 2015 ). These observations clearly suggest that food consumption can indirectly alter the melatonin-related receptor GPR50 and thus likely shape unique network properties of the circadian clock in the hypothalamus and/or peripheral tissues where the circadian clock is cell-autonomous (Bechtold et al, 2012 ).…”