SIRT6, a Mammalian Deacylase with Multitasking Abilities

Abstract

Mammalian sirtuins have emerged in recent years as critical modulators of multiple biological processes, regulating cellular metabolism, DNA repair, gene expression, and mitochondrial biology. As such, they evolved to play key roles in organismal homeostasis, and defects in these proteins have been linked to a plethora of diseases, including cancer, neurodegeneration, and aging. In this review, we describe the multiple roles of SIRT6, a chromatin deacylase with unique and important functions in maintaining cellular homeostasis. We attempt to provide a framework for such different functions, for the ability of SIRT6 to interconnect chromatin dynamics with metabolism and DNA repair, and the open questions the field will face in the future, particularly in the context of putative therapeutic opportunities.

Sirt6 inhibition delays the onset of experimental autoimmune encephalomyelitis by reducing dendritic cell migration

“…*p < 0.05, **p < 0.01 (n = 6 from two independent experiments). Data were analyzed by t test SIRT6 plays critical roles in multiple molecular pathways, including DNA repair, telomere maintenance, glycolysis, gluconeogenesis, lipid metabolism, and inflammation [25]. Different attempts to modulate its activity have been investigated as a means to provide therapeutic benefits in different conditions.…”

“…Different attempts to modulate its activity have been investigated as a means to provide therapeutic benefits in different conditions. Mainly in view of its role in DNA repair and in telomere biology and as a tumor suppressor in different cancer type, activation of SIRT6 is postulated to have beneficial effects and to promote healthspan [25]. Nevertheless, the development of SIRT6 inhibitors has also been pursued Fig.…”

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

“…Our approach successfully predicted a cryptic allosteric site on Sirt6, a critical target that is involved in various physiological and pathological processes, such as longevity and carcinogenesis. However, there is a lack of specific therapeutic agents for Sirt6 [32][33][34]38 . Sirt6 belongs to the "magnificent seven" sirtuin family (Sirt1 to Sirt7).…”

“…Sirtuins, which are nicotinamide adenine dinucleotide (NAD + )-dependent class III histone deacetylases (HDACs), deacetylate histones and mediate various cellular events ranging from maintenance of genomic stability to metabolic activities [30][31][32][33][34] . Sirt6, a member of the sirtuin family (Sirt1-7), catalyzes the removal of acetyl groups from the lysine residues 9, 18, and 56 on histone 3 (H3K9, H3K18, and H3K56) and transfers them to NAD + cofactor.…”

“…Thus, Sirt6 is a potential therapeutic target [32][33][34]38 . There are limited selective compounds for drugging Sirt6 owing to the highly conserved structural architecture among its paralogues.…”