Transcriptional targets of sirtuins in the coordination of mammalian physiology

Abstract

Sirtuins (Sirts) compose a family of NAD(+)-dependent deacetylases and/or ADP-ribosyltransferases, which have been implicated in aging, metabolism, and tolerance to oxidative stress. Many of the biological processes regulated by Sirts result from the adaptation of complex gene-expression programs to the energetic state of the cell, sensed through NAD(+) levels. To that respect, Sirts, and particularly the founding member of the family Sirt1, have emerged as important regulators of transcription, which they modulate both positively and negatively by targeting histones and transcriptional complex regulatory proteins. This review will focus on recent advances that have started deciphering how mammalian Sirts regulate transcriptional networks and thereby control physiology.

Figure 1. Sirtuins catalyze deacetylation and/or O-ADP-ribosylation reactions

The two enzymatic reactions catalyzed by sirtuins use nicotinamide-adenine-dinucleotide (NAD⁺) as a cofactor and produce nicotinamide (NAM). In the deacetylation reaction, the acetyl group of a target lysine residue is transferred to the ADP-ribose moiety of NAD⁺ to generate 2’-O-acetyl-ADP-ribose. Sirtuins can also catalyze the mono ADP-ribosylation of a non-acetylated protein substrate by transferring the ADP-ribose moiety of NAD⁺ to the target protein. The principal reaction of each sirtuin is depicted but it should be noted that most sirtuins harbor both activities to different degrees. For example, Sirt6 also has a weak deacetylase activity while Sirt1, Sirt2 and Sirt3 can catalyze O-ADP-ribosylation. The reactions catalyzed by Sirt7 remain to be determined.

Figure 2. Transcriptional targets of sirtuins

The main molecular mechanisms through which sirtuins regulate gene expression are depicted according to the nature of the transcriptional regulator interacting with sirtuins, and to the action that sirtuins exert on the activity of this factor. Transcriptional activation mediated by sirtuins (indicated by green boxes) can result both from the enhanced activity of a transcriptional activator and from the inhibition of a repressor, although examples of this latter case have not been documented to date. In contrast, Sirt-mediated transcriptional repression (indicated by red boxes) is caused both by enhanced repressor activity and from the inhibition of an activator. Abbreviations are PPAR: peroxisome proliferator-activated receptor; NCoR: nuclear corepressor; COUP-TF: chicken ovalbumin upstream promoter transcription factor; CTIP2: COUP-TF-interacting protein 2; Suv39H1: suppressor of variegation 3–9 homologue 1; PGC-1α: PPARγ coactivator 1 α; LXR: liver X receptor; FOXO: Forkhead Box class O; Tat: transactivator; Pol I: RNA polymerase I; NFκB: nuclear factor κ B; AR: androgen receptor; ER: estrogen receptor; MyoD: myoblast determination protein 1; p/CAF: p300/CBP-associated factor; TAF_I68: TATA box binding protein-associated factor I 68.