PARP around the clock

Abstract

Cells possess internal ∼24 hr or circadian clocks that synchronize physiological processes with daily cycles of light and nutrient availability. In this issue, Asher et al. (2010) find that PARP-1 (poly(ADP-ribose) polymerase 1) modifies components of the clock machinery in response to feeding, providing a mechanism for how metabolic rhythms coordinate with circadian rhythms.

Figure 1. PARP-1 links the circadian clock with metabolic rhythms

(A) The molecular clock in cells is composed of an autoregulatory feedback loop that takes ~24 hours to complete. The transcription factor CLOCK and BMAL1 bind to E-boxes and activate the negative arm of the feedback loop by triggering gene expression of their own repressors, Cryptochrome (Cry) and Period (Per). In response to feeding, PARP-1 poly-ADP-ribosylates (i.e., PARlyates) CLOCK (Asher et al. 2010), which inhibits DNA binding by CLOCK/BMAL1. In contrast, Sirtuin I (SIRT1) modulates BMAL1 by deacetylating it. (B) Circadian rhythms exert a strong influence over metabolic rhythms by controlling the timing of behaviors, such as feeding and sleep. Metabolic genes, such as AMP-activated protein kinase (AMPK) regulate levels of NAD⁺ and are themselves under circadian control. The activities of PARP-1 and SIRT1 are directly modulated by NAD⁺, and these enzymes feedback to regulate circadian genes.