Figure 2.

The mutual regulatory mechanisms between sirtuins and the circadian clock. NAD⁺ is a cellular energy sensor and sirtuins use NAD⁺ as a co-factor. The circadian clock regulates the activity of sirtuins through multiple mechanisms, including indirectly modulating sirtuin activity by controlling the rhythmic expression of Nampt to regulate NAD⁺ oscillation levels and directly influencing the transcription of the Sirt1 or SIRT1 protein. SIRT1, in turn, interacts with CLOCK-BMAL1 to affect circadian rhythm amplitude and gene expression by deacetylating PER2, BMAL1, and histone H3 at circadian gene promoters. In contrast to SIRT1, SIRT6 interacts with CLOCK-BMAL1 and governs their chromatin recruitment to circadian gene promoters. SIRT6 can also affect the circadian clock by deacetylating PER2, whereas SIRT7 contributes to circadian clock regulation by deacetylating CRY1. NAM, nicotinamide; NMN, nicotinamide mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NMNAT1-3, nicotinamide mononucleotide adenyltransferase; Ac, acetylation; dinusoidal lines represent rhythmic mRNAs; arrows depict the synthesis, assembly, and/or localization of clock proteins; the blocked line denotes repression.