As“SIRT”ing the role of an epigenetic modifier in hematopoietic stem cell homeostasis

Mammalian Sirtuin protein family consists of SIRT1-SIRT7. Sirtuins are NAD+-dependent histone deacetylases (HDACs) known to regulate metabolic homeostasis, chromatin structure and DNA repair thereby regulating genomic stability. They were first discovered in yeast as silent information regulator 2 (Sir2) that promote longevity (1). Subcellular localization of sirtuins varies depending on the type of cell and the function associated with the sirtuin. For most part, SIRT1 is nuclear and mediates the effects of calorie restriction which reduces tumor formation and stress-induced apoptosis. SIRT1 also mediates cancer drug resistance. SIRT2 is predominantly cytoplasmic and regulates oxidative stress. SIRTs 3, 4 and 5 are in mitochondria and regulate mitochondrial functions such as energy usage. SIRT6 is nuclear and regulates DNA repair and SIRT7 is nucleolar regulating rRNA transcription (2). SIRTs 4 and 5 have weak deacetylase activity but SIRT4 has ADP-ribosylase activity and SIRT5 has demalonylase and desuccinylase activities. Besides deacetylation, SIRT6 also regulates TNFα secretion by modulating its lysine fatty acylation (3).