Beauharnois Jade M, Bolívar Beatriz E, Welch John T
Department of Chemistry, University at Albany, SUNY, Albany, NY 12222, USA.
Mol Biosyst. 2013 Jul;9(7):1789-806. doi: 10.1039/c3mb00001j. Epub 2013 Apr 17.
Sirtuins, possessing either histone deacetylase or mono-ribosyltransferase activity, regulate important pathways in bacteria, archaea and eukaryotes. SIRT6, an enzyme highly expressed in skeletal muscles, brain, heart, liver, and thymus, affects transcriptional regulation in a tissue-specific manner. This enzyme has a two-domain structure that consists of a large Rossmann fold and a smaller and structurally more varied sequence containing a Zn(2+)-binding motif. The C-terminus is required for proper nuclear localization, while the N-terminus is important for chromatin association and for intrinsic catalytic activity. SIRT6 promotes resistance to DNA damage and oxidative stress, the principal defects associated with age-related diseases. The modulation of aging and other metabolic functions by SIRT6 may be indicative of previously unrecognized regulatory systems in the cell. The propensity of individual SIRT6 molecules to undergo intramolecular mono-ADP-ribosylation, suggests this auto-ribosylation may contribute to the self-regulation of SIRT6 function. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear. It was known that, similar to the yeast Sir2 protein, human SIRT6 deacetylates histones and regulates DNA stability and repair; however, new mechanistic insights can be derived from the discovery of the highly substrate-specific histone deacetylase activity of SIRT6. This deacetylase activity promotes proper chromatin function in several physiologic contexts, to include telomere and genome stabilization, gene expression and DNA repair. By maintaining both the integrity and the expression of the mammalian genome, SIRT6 may help prevent cellular senescence. Moreover, successful molecular modulation of SIRT6 activity may lead to the development of new chemotherapeutic modalities. The action of SIRT6 is described in this review, with an emphasis on the cellular roles of the enzyme and the relation of those enzymatic functions to human biology and disease.
沉默调节蛋白具有组蛋白脱乙酰酶或单核糖基转移酶活性，可调节细菌、古细菌和真核生物中的重要途径。SIRT6是一种在骨骼肌、大脑、心脏、肝脏和胸腺中高度表达的酶，以组织特异性方式影响转录调控。这种酶具有双结构域结构，由一个大的Rossmann折叠和一个较小且结构更多样化的序列组成，该序列包含一个锌离子结合基序。C末端是正确的核定位所必需的，而N末端对于染色质结合和内在催化活性很重要。SIRT6可增强对DNA损伤和氧化应激的抵抗力，而DNA损伤和氧化应激是与年龄相关疾病相关的主要缺陷。SIRT6对衰老和其他代谢功能的调节可能表明细胞中存在以前未被认识的调节系统。单个SIRT6分子发生分子内单ADP核糖基化的倾向表明这种自身核糖基化可能有助于SIRT6功能的自我调节。直到最近，SIRT6还是一种催化活性和底物尚不清楚的孤儿酶。已知与酵母Sir2蛋白类似，人类SIRT6可使组蛋白脱乙酰基并调节DNA稳定性和修复；然而，SIRT6高度底物特异性组蛋白脱乙酰酶活性的发现可以带来新的机制见解。这种脱乙酰酶活性在多种生理环境中促进适当的染色质功能，包括端粒和基因组稳定、基因表达和DNA修复。通过维持哺乳动物基因组的完整性和表达，SIRT6可能有助于预防细胞衰老。此外，成功地对SIRT6活性进行分子调节可能会导致开发新的化疗方法。本文综述了SIRT6的作用，重点介绍了该酶的细胞作用以及这些酶促功能与人类生物学和疾病的关系。
