Ed further light on SIRT6 cancer biology and proposed as potential new generation anticancer therapeutics. Keywords: NAD+ -dependent deacylases; cell death modulation; SIRT6 modulators; cancer; epigeneticsPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.1. Introduction Sirtuin 6 (SIRT6) can be a crucial chromatin regulating protein belonging to the Sirtuin (SIRT) family members, a class of broad-spectrum protein deacylases that utilize NAD+ as cosubstrate [1]. Sirtuins have been initially classified as class III histone deacetylases (HDACs), indeed SIRT6 has been shown to catalyze the deacetylation of lysines K9, K18, and K56 of histone H3 [2]. Nonetheless, SIRT6 promotes diverse reactions on a wide range of substrates beyond histones [6]. As well as protein deacetylation, SIRT6 catalyzes the protein deacylation of long-chain fatty acyl groups in the -amino groups of lysines as well as the mono-ADP-ribosylation of lysine and arginine residues of chromatin silencing DNA repair proteins [7].Copyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is definitely an open access post distributed under the terms and circumstances with the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).Cancers 2021, 13, 1156. https://doi.org/10.3390/cancershttps://www.mdpi.com/journal/cancersCancers 2021, 13,2 ofSIRT6 expression is almost ubiquitous, with all the highest levels detected in skeletal muscle, heart, brain, liver, kidney, and IP Antagonist Storage & Stability thymus [8,9]. SIRT6-catalyzed deacetylation is linked with compaction of chromatin and consequent transcriptional repression, as well as response to DNA harm. Notably, current reports indicated that the SIRT6 deacetylase catalytic activity is one hundred to 1000 times reduce than that on the most active SIRTs [10]. The deacylase efficiency of SIRT6 has been shown to be higher compared to deacetylation, which might be in turn activated by endogenous ligands including no cost fatty acids (FFA) [11,12]. Certainly, in vitro demyristoylation activity is roughly 300 instances larger than deacetylation. Alternatively, most of SIRT6 cellular functions described to date are related to its deacetylation activity, as opposed to deacylation, which has been established inside the case of TNF- [12] and R-Ras2 [13]. These features, in addition to the ability of SIRT6 to catalyze mono-ADP-ribosylation, depict a difficult picture of its biological functions and associated phenotypes. The capability of SIRT6 to regulate unique molecular pathways is pivotal to maintain cellular homeostasis [6]. Upon DNA damage, an increase of SIRT6 levels determines an improvement of chromatin accessibility recruiting various DNA repair variables, for example 53BP1, BRCA1, and RPA towards the breakpoint [14]. SIRT6 modulates double strand break (DSB) repair activating each non-homologous end-joining (NHEJ) and homologous recombination (HR), via the interaction with various proteins involved in these molecular pathways [15]. For example, beneath KDM1/LSD1 Inhibitor drug oxidative anxiety SIRT6 associates with the poly[ADPribose]polymerase PARP1 and catalyzes its mono-ADP-ribosylation, thereby stimulating its activity and resulting in enhanced DSB repair [16]. SIRT6 can also be involved within the base excision repair (BER) method within a PARP1-dependent manner [17] and contributes to genome and telomeres integrity in mammalian cells by means of the interaction with the DNA glycosylase MYH plus the endonuclease APE1 [18].
