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

Published

May 28, 2015

Author(s)

Geoffrey B. McFadden, Augustin Luna, Mirit I. Aladjem, Kurt W. Kohn

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 circadian clock and the mechanism through which this effect operates remains to be thoroughly investigated. Here we build an in silico model to examine the observed behavior by investigating a possible mechanism building on evidence linking circadian rhythms to metabolism. The proposed mechanism 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 findings that show 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 that PARP1 is a major consumer of NAD during DNA damage response. In our simulation, we observe that increased PARP1 activity may be able to trigger the observed phase advancements by downregulating SIRT1 activity through its competition for NAD supplies. We show how this mechanism may operate through acetylation events in conjunction with phosphorylation events that have also been predicted to be involved in the observed behavior. These findings suggest a possible mechanism through which multiple perturbations each dominant during different points of the circadian cycle may account for the observed behavior resulting in the primarily phase advancement response seen during DNA damage perturbations of the circadian clock.

Citation

PLoS One

Pub Type

Journals

Download Paper

Local Download

Keywords

circadian rhythms, DNA damage response, SIRT1 and PARP1 activity, MEM diagram, phase response curves, ODE model

Citation

McFadden, G. , Luna, A. , Aladjem, M. and Kohn, K. (2015), Predicted Role of NAD Utilization in the Control of Circadian Rhythms During DNA Damage Response, PLoS One, [online], https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=914040 (Accessed December 30, 2024)