Poly(ADP-Ribose) Polymerase 1 Participates in the Phase Entrainment of Circadian Clocks to Feeding

Abstract

Circadian clocks in peripheral organs are tightly coupled to cellular metabolism and are readily entrained by feeding-fasting cycles. However, the molecular mechanisms involved are largely unknown. Here we show that in liver the activity of PARP-1, an NAD(+)-dependent ADP-ribosyltransferase, oscillates in a daily manner and is regulated by feeding. We provide biochemical evidence that PARP-1 binds and poly(ADP-ribosyl)ates CLOCK at the beginning of the light phase. The loss of PARP-1 enhances the binding of CLOCK-BMAL1 to DNA and leads to a phase-shift of the interaction of CLOCK-BMAL1 with PER and CRY repressor proteins. As a consequence, CLOCK-BMAL1-dependent gene expression is altered in PARP-1-deficient mice, in particular in response to changes in feeding times. Our results show that Parp-1 knockout mice exhibit impaired food entrainment of peripheral circadian clocks and support a role for PARP-1 in connecting feeding with the mammalian timing system.

The Mammalian Circadian Timing System: Synchronization of Peripheral Clocks

“…Hence, the regulation of their circadian production and secretion appears to be dominated by the SCN, which does not adapt its phase to inverted feeding rhythms. Similar to the observations made with PARP-1 knockout mice (Asher et al 2010), the disruption of the glucocorticoid receptor (GR) in hepatocytes affects the kinetics of phase shifting induced by the inversion of the feeding cycle. However, in stark contrast to PARP-1 loss of function, the depletion of GR accelerates the food-induced phase resetting (Fig.…”

“…Another NAD þ -dependent enzyme, poly(ADP-ribose) polymerase 1 (PARP-1), has recently been implicated in the phase resetting of liver clocks. PARP-1 adds poly(ADP-ribose) residues to itself and to CLOCK in a diurnal manner, and whereas PARP-1 has little effect on circadian gene expression in animals kept under normal conditions, it does affect the kinetics of phase adaptation to feeding rhythms (Asher et al 2010).…”

“…Other posttranslational modifications have also been found on core clock proteins. Thus, CLOCK can be sumoylated (Cardone et al 2005) (Asher et al 2010). PER2 and BMAL1 can be acetylated (by CLOCK [Doi et al 2006;Grimaldi et al 2009] and, probably, additional acetyltransferases) and deacetylated in a circadian fashion by the NAD þ -dependent deacetylase Sirtuin 1 (SIRT1) (Asher et al 2008;Nakahata et al 2008).…”

The role of clock genes and rhythmicity in the liver

“…Asher and coworkers showed that the activity of poly(ADP-ribose) polymerase 1 (PARP-1) is rhythmic in the liver and that it is regulated by feeding (Asher et al, 2010). Interestingly, Parp-1 knockout mice exhibit impaired food entrainment of peripheral clocks, suggesting PARP-1 as a mediator of food entrainment.…”

Horloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux

“…Par ailleurs, la désacétylation de Per2 par Sirt1 conduit à sa dégradation par le protéasome. Le NAD + est également le cofacteur de la polyADP-ribose polymérase-1 (PARP-1), dont l'expression oscille de façon circadienne et varie en fonction de la prise de nourriture (qui module quant à elle l'activité de CLOCK) [27]. Par ailleurs, une augmentation du rapport AMP/ATP, témoin d'un ralentissement du métabolisme se produisant en situation de jeûne et au cours de l'exercice, active l'AMP activated protein kinase (AMPK) qui, en retour, phosphoryle Cry [28], favorisant ainsi sa dégradation par la protéine FBXL3 (F-box and leucine-rich repeat protein 3) et le protéasome.…”