The human sirtuin family: Evolutionary divergences and functions
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The human sirtuin family: Evolutionary divergences and functions Athanassios Vassilopoulos,1 Kristofer S. Fritz,2 Dennis R. Petersen2 and David Gius1,3* 1
Department of Radiation Oncology and Vanderbilt University Medical Center, Nashville, TN 37232, USA Department of Pharmaceutical Sciences, Graduate Program in Toxicology, School of Pharmacy, University of Colorado Denver, Aurora, CO 80045, USA 3 Departments of Cancer Biology, Pediatric and Radiation Oncology, and Vanderbilt University Medical Center, Nashville, TN 37232, USA *Correspondence to: Tel: þ1 615 322 2555; E-mail: [email protected] 2
Date received (in revised form): 9th June 2011
Abstract The sirtuin family of proteins is categorised as class III histone deacetylases that play complex and important roles in ageing-related pathological conditions such as cancer and the deregulation of metabolism. There are seven members in humans, divided into four classes, and evolutionarily conserved orthologues can be found in most forms of life, including both eukaryotes and prokaryotes. The highly conserved catalytic core domain composed of a large oxidised nicotinamide adenine dinucleotide (NADþ)-binding Rossmann fold subunit suggests that these proteins belong to a family of nutrient-sensing regulators. Along with their function in regulating cellular metabolism in response to stressful conditions, they are implicated in modifying a wide variety of substrates; this increases the complexity of unravelling the interplay of sirtuins and their partners. Over the past few years, all of these new findings have attracted the interest of researchers exploring potential therapeutic implications related to the function of sirtuins. It remains to be elucidated whether, indeed, sirtuins can serve as molecular targets for the treatment of human illnesses. Keywords: Evolution, histone deacetylases, human diseases, metabolism, sirtuins
Introduction 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 transcriptionfactor 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 nonhistone 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 The sirtuin family of proteins is highly conserved, both fu
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