SIRT7 Acts as a Guardian of Cellular Integrity by Controlling Nucleolar and Extra-Nucleolar Functions

Abstract

Sirtuins are key players for maintaining cellular homeostasis and are often deregulated in different human diseases. SIRT7 is the only member of mammalian sirtuins that principally resides in the nucleolus, a nuclear compartment involved in ribosomal biogenesis, senescence, and cellular stress responses. The ablation of SIRT7 induces global genomic instability, premature ageing, metabolic dysfunctions, and reduced stress tolerance, highlighting its critical role in counteracting ageing-associated processes. In this review, we describe the molecular mechanisms employed by SIRT7 to ensure cellular and organismal integrity with particular emphasis on SIRT7-dependent regulation of nucleolar functions.

Keywords: SIRT7; deacetylation; nucleolus; sirtuins; stress responses.

Figure 1

Mammalian sirtuins: general functions and activation in response to stress (a) Schematic representation of the main enzymatic activities of mammalian sirtuins. Sirtuins catalyze deacetylation of protein targets by transferring the acetyl group to NAD+, concomitant with the release of nicotinamide (NAM) and 2′-O-acetyl-ADP-ribose (upper panel). In the mono-ADP-ribosylation reaction, the ADP-ribose (ADPR) is transferred from NAD⁺ to the substrate, leading to release of NAM (lower panel). NAM is a potent inhibitor of the enzymatic activity of sirtuins. (b) Schematic representation of the structure and subcellular distribution of mammalian sirtuins. SIRT7 nuclear and nucleolar localization sequences (NLS and NoLS, respectively) are indicated. (c) Scheme depicting the mechanisms involved in sirtuins activation following stress (red) and their main biological functions (green).

Figure 2

SIRT7 has a dual function in the unstressed nucleolus. SIRT7 stimulates rDNA transcription by facilitating recruitment of Pol I both by interacting with UBF1 and through direct deacetylation of the Pol I subunit PAF53. In addition, SIRT7 deacetylates fibrillarin (FBL) and thereby favors FBL-mediated chromatin remodeling required for stimulation of rDNA transcription. SIRT7 also promotes pre-rRNA processing by deacetylating U3–55k, a core component of the U3 snoRNP complex. SIRT7 is a key player for maintaining rDNA stability at inactive rDNA genes by promoting heterochromatin formation through recruitment of SIRT1, DNMT1, and the chromatin remodeling complex (NORC). Moreover, SIRT7 might maintain rDNA stability by facilitating resolution of R-loops.

Figure 3

SIRT7 promotes p53 stabilization in response to distinct stressors. In response to UV-induced stress, SIRT7 is activated by ATR-mediated phosphorylation. Activated SIRT7 efficiently deacetylates its nucleolar target nucleophosmin (NPM), facilitating its exclusion from nucleoli. Deacetylated NPM binds and inhibits the ubiquitin ligase MDM2, thereby preventing MDM2- dependent ubiquitination and subsequent proteasomal degradation of p53 (left panel). In response to glucose starvation, SIRT7 translocates from the nucleolus, associates and deacetylates PCAF, which favors PCAF-mediated degradation of MDM2, leading to p53 stabilization (right panel).

Figure 4

Translocation of SIRT7 from the nucleolus following stress is a critical event to activate SIRT7-regulated extra-nucleolar functions. See text for details.