The diversity of histone versus nonhistone sirtuin substrates

Abstract

The members of the Sir2 family, or sirtuins, are major regulators of the response to different types of stress. The members of the family have adapted to increasing complexities throughout evolution and have become diversified by increasing their number, specificity, and localization and acquiring novel functions. Sirtuins have been consistently implicated in the cross-talk between the genomic information and environment from the prokaryotes onward. Evidence suggests that in the transition to eukaryotes, histones became one of the basic and most conserved targets of the family, to the extent that in yeast and mammals, sirtuins were originally described as NAD(+)-dependent histone deacetylases and classified as class III histone deacetylases. A growing number of studies have determined that sirtuins also target a wide range of nonhistone proteins. Many of these targets are also directly or indirectly related to chromatin regulation. The number of targets has grown considerably in the last decade but has provoked an ill-founded discussion that neglects the importance of histones as sirtuin targets. In this review, we summarize our knowledge regarding the range of sirtuin targets described to date and discuss the different functional implications of histone and nonhistone targets throughout evolution.

Keywords: SIRT1-SIRT7; deacetylation; epigenetics; genome stability; histones; sirtuins; stress response.

Figure 1.

Classification of sirtuin family. The representation includes a list of sirtuins from selected organisms (bacteria to humans) classified phylogenetically according to Frye. The schematic shows the general location of each sirtuin. The color each representing a sirtuin belongs to a different class of sirtuins (I-IV), and their color intensity suggests their stage of evolution from light to dark (from lower to higher eukaryotes, respectively). Δ = the current knowledge of their NAD⁺-dependent deacetylase activity; * = their known ADP-ribosyltransferase activity.

Figure 2.

Sirtuin functions and targets in the cell. The figure mainly shows sirtuin chromatin–related functions that complement each other or differently regulate the same process.

Figure 3.

Protein alignments using ClustalW. (A) Histone H3 alignment: alignment among eukaryotes versus archaea H3. (B) Alignment between archaea Alba protein and human histone H4. As it is shown, the sequence around the K16 residue is conserved in both cases. (C) FOXO protein alignment (fragment) from S. cerevisiae (Hcm1p) and C. elegans (Daf-16) to human homologs. The lysines known to be deacetylated by sirtuins in any of them are highlighted. (D) Alignment of p300 using S. cerevisiae (Rtt109p), Ostreococcus, C. elegans (cpb-1), and human homologs. Alignment of 2 different regions of the p300 homologs containing SIRT1 and SIRT2 lysine targets.