The human sirtuin family: Evolutionary divergences and functions

Epigenetic modifications of protein, histone and chromatin play an important role in regulating gene expression, cancer formation and life span. Acetylation is a major player in epigenetic modifications, resulting in open chromatin structures and, hence, permissive conditions for transcription-factor recruitment to the promoters, followed by initiation of transcription. By contrast, histone deacetylases (HDACs) oppose the activity of histone acetyltransferases by removing the acetyl groups from lysine residues within specific promoters, leading to gene silencing [1]. In addition, many non-histone proteins have been identified as substrates of HDACs, implicating acetylation as a post-translational modification that affects various aspects of cell physiology [2]. There are two protein families having HDAC activity: the classical HDAC family, which consists of two different phylogenetic classes (class I and class II); and the sirtuin family of proteins, which requires the co-factor nicotinamide adenine dinucleotide (NAD) for its deacetylase activity [3,4].The sirtuin family of proteins is highly conserved, both functionally and structurally. Its members are integrated into most forms of life, including eubacteria, archaea and eukaryotes, and therefore predate both histone and chromatin formation [5]. Sirtuins have been involved in metabolic and chromatin regulation throughout evolution, dating back to the first examples of chromatin-like organisation of DNA in archaea [6,7]. The silent information regulator 2 gene (Sir2) was first discovered in Saccharomyces cerevisiae and was named after its ability to relieve gene silencing [8]. Once discovered, sirtuins were rapidly characterised in yeast, bacteria, plants and mammals.Sirtuins belong to the deoxyhypusine synthase (DHS)-like NAD/flavin adenine dinucleotide (FAD)-binding domain clan and all members contain the Rossmann fold structural motif, which can be found in proteins that bind nucleotides. The other members of th