去乙酰化酶(Sirtuins),新陈代谢和 DNA 修复

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Sirtuins, Metabolism, and DNA repair

Abstract

摘要

Cells evolve to actively coordinate nutrient availability with cellular activity in order to maintain metabolic homeostasis. In addition, active pathways to repair DNA damage are crucial to avoid deleterious genomic instability. In recent years, it has become increasingly clear that availability of intermediate metabolites may play an important role in DNA repair, suggesting that these two seemingly distant cellular activities may be highly coordinated. The sirtuin family of proteins now described as deacylases (they can also remove acyl groups other than acetyl moieties), it appears to have evolved to control both metabolism and DNA repair. In this review, we discuss recent advances that lay the foundation to understanding the role of sirtuins in these two biological processes, and the potential crosstalk to coordinate them.

细胞进化,积极协调营养物质的可用性和细胞活动,以维持代谢稳态。此外,活性途径修复 DNA 损伤是至关重要的,以避免有害的基因组不稳定性。近年来,人们越来越清楚地认识到,中间代谢物的存在可能在 DNA 修复中发挥重要作用,这表明这两种看似遥远的细胞活动可能是高度协调的。Sirtuin 蛋白家族现在被描述为脱酰基酶(它们也可以除去乙酰基部分以外的酰基基团) ,它似乎已经进化到控制新陈代谢和 DNA 修复。在这篇综述中,我们讨论了最近的进展,奠定了基础,了解去乙酰化酶在这两个生物过程中的作用,以及潜在的串扰协调他们。Go to: 去:

Introduction

引言

Sirtuins are members of a family of evolutionarily conserved enzymes with NAD+-dependent deacylase activity. Since the discovery of Sir2 (silencing information regulator 2) in the budding yeast Saccharomyces cerevisiae as a transcriptional silencer of the mating-type loci more than 20 years ago [1], many studies have demonstrated diverse biological roles for sirtuins, such as in genome stability, cellular metabolism, and lifespan regulation [2,3]. Mammalian sirtuins have seven isoforms (SIRT1–7), each one with unique subcellular localization and distinct functions [4]. SIRT1 and SIRT2 can be found in both nucleus and cytoplasm, SIRT6 and SIRT7 are almost exclusively nuclear and SIRT3, SIRT4, and SIRT5 are located in the mitochondria [5]. Studies on sirtuin biology have shown great progress in the past two decades, emphasizing the critical importance of these enzymes in human biology and disease.

Sirtuins 属于具有 NAD + 依赖脱酰化酶活性的进化保守酶家族。自从20多年前在芽殖酵母中发现 Sir2(沉默信息调节因子2)作为交配型位点的转录沉默酿酒酵母以来,许多研究已经证明了 sirtuins 的多种生物学作用,如基因组稳定性、细胞代谢和寿命调节[2,3]。哺乳动物去乙酰化酶有七种亚型(SIRT1-7) ,每一种都具有独特的亚细胞定位和不同的功能[4]。SIRT1和 SIRT2分别存在于细胞核和细胞质中,SIRT6和 SIRT7基本上都是细胞核,而 SIRT3、 SIRT4和 SIRT5则位于线粒体中。去乙酰化酶生物学的研究在过去的二十年中取得了巨大的进展,强调了这些酶在人类生物学和疾病中的关键重要性。

Due to their NAD+ dependency, it had been speculated that sirtuins play a crucial role in modulating energy metabolism. Indeed, sirtuins are broadly recognized as critical regulators of multiple metabolic pathways, including glucose, glutamine, and lipid metabolism [6]. For cells to thrive, energy and metabolic demands have to be carefully coordinated with nutrients availability. As sensors of energy and redox status in cells, these protein deacylases can directly modulate activity of key metabolic enzymes -by posttranslational modifications- as well as regulate transcription of metabolic genes. In addition, several sirtuins play additional roles in metabolic homeostasis. For instance, both SIRT1 and SIRT2 control autophagy responses under various nutrient stress conditions, as modulators of FOXO signaling pathway [7]. Autophagy will be covered in detail in an accompanying article in this issue.

由于它们对 NAD + 的依赖性,人们推测去乙酰化酶在调节能量代谢中起着至关重要的作用。事实上,去乙酰化酶被广泛认为是多种代谢途径的关键调节剂,包括葡萄糖、谷氨酰胺和脂质代谢。为了使细胞茁壮成长,能量和新陈代谢的需求必须小心地与营养物质的供应相协调。作为细胞能量和氧化还原状态的传感器,这些蛋白质脱酰基酶可以通过翻译后修饰直接调节关键代谢酶的活性,也可以调节代谢基因的转录。此外,一些去乙酰化酶在代谢稳态中发挥额外的作用。例如,SIRT1和 SIRT2作为 FOXO 信号通路的调节器,在各种营养胁迫条件下控制自噬反应[7]。自噬将在本期的一篇附带文章中详细讨论。

Nuclear sirtuins have also evolved as regulators of genome integrity. Our cells experience ~ 1×104−1×105DNA lesions per day [8], hence they have developed repair machineries to avoid detrimental outcomes from oxidative and genotoxic stress. In the past decade, the roles of sirtuins in maintaining genomic stability have been described, as regulators of DNA repair pathways [9], chromatin structure [10], and telomere maintenance [11,12].

核去乙酰化酶也作为基因组完整性的调节因子进化而来。我们的细胞每天经历 ~ 1 × 104-1 × 105个 DNA 损伤[8] ,因此它们开发了修复机制,以避免氧化和基因毒性应激造成的有害后果。在过去的十年中,去乙酰化酶在维持基因组稳定性方面的作用被描述为 DNA 修复途径的调节剂[9] ,染色质结构[10]和端粒维持[11,12]。

Based on the fact that sirtuins possess dual roles in metabolism and DNA repair, sirtuins can serve as nodal points in regulating both processes. Intriguingly, new studies have started to appreciate that DNA damage can directly trigger adaptive metabolic responses [13,14], indicating that these two seemingly separate biological entities may function in a highly coordinated fashion. In this review, we will focus on recent progress in understanding the roles of sirtuins in both metabolism and DNA repair, and the possible crosstalk between these two phenomena.

基于去乙酰化酶在新陈代谢和 DNA 修复中具有双重作用这一事实,去乙酰化酶可以作为调节这两个过程的节点。有趣的是,新的研究已经开始认识到 DNA 损伤可以直接触发适应性代谢反应[13,14] ,这表明这两个看似独立的生物实体可能以一种高度协调的方式运作。在这篇综述中,我们将重点介绍在了解去乙酰化酶在代谢和 DNA 修复中的作用方面的最新进展,以及这两种现象之间可能的交叉。Go to: 去:

Sirtuins in metabolism

代谢中的去乙酰化酶

Glucose and glutamine metabolism

葡萄糖和谷氨酰胺代谢

Since glucose is a primary nutrient for cell survival and proliferation, systemic glucose levels should be tightly regulated throughout tissues. Crucial organs such as liver, muscle, and pancreas are main modulators of glucose homeostasis. At the cellular level, once glucose enters a cell, it is converted into pyruvate in the cytoplasm through glycolysis in a multi-enzyme, strictly regulated process. In most cells, pyruvate will then enter the TCA cycle to generate energy through oxidative phosphorylation (OXPHOS) in a highly efficient process (34–36 mols of ATP per mol of glucose). However, in specific cases, pyruvate will be diverted in the cytoplasm to produce lactate, a less efficient way to produce ATP, but a critical adaptive mechanism in cells where OXPHOS is impeded (hypoxia, for instance) or to produce intermediate metabolites for biomass in highly proliferating cells.

由于葡萄糖是细胞存活和增殖的主要营养物质,全身葡萄糖水平应该在整个组织中受到严格控制。重要器官如肝脏、肌肉和胰腺是葡萄糖稳态的主要调节器官。在细胞水平上,一旦葡萄糖进入细胞,它通过糖酵解在细胞质中转化为丙酮酸,这是一个多酶、严格调节的过程。在大多数细胞中,丙酮酸会进入 TCA 循环,通过氧化磷酸化产生能量,这是一个高效的过程(每摩尔葡萄糖含有34-36 mmol 的 ATP)。然而,在特定的情况下,丙酮酸会在细胞质中转移以产生乳酸,这是一种产生 ATP 的低效方式,但是在 OXPHOS 受阻的细胞中(例如缺氧)是一种关键的适应机制,或者在高度增殖的细胞中产生生物量的中间代谢物。

Extensive studies have previously shown that SIRT1 can modulate both gluconeogenesis and glycolysis by regulating important metabolic factors, including PGC1α and FOXO [15]. More recently, intracellular levels of NAD+ has been shown to regulate SIRT1 deacetylase activity, affecting high fat diet (HFD)-induced obesity and aging, as discussed below [reviewed in 16].

广泛的研究以前已经表明,SIRT1可以调节糖异生和糖酵解,通过调节重要的代谢因子,包括 pgc1α 和 FOXO [15]。最近,细胞内 NAD + 水平被证明可以调节 SIRT1去乙酰化酶活性,影响高脂饮食(HFD)诱导的肥胖和衰老,如下文[16]所述。

SIRT3 is a major mitochondrial protein deacetylase [17], regulating multiple metabolic proteins such as the TCA cycle protein isocitrate dehydrogenease 2 (IDH2) [18] and key proteins in the electron transfer chain (ETC) [1921]. In skeletal muscle, SIRT3 plays an important role in regulating metabolic adaptive responses. Decreased levels of SIRT3 cause increasing oxidative stress and insulin resistance [22] and recent studies showed that active deacetylation of pyruvate dehydrogenase (PDH) E1α by SIRT3 provides metabolic flexibility under nutrient stress conditions [23]. Wang and his colleagues discovered that SIRT3 can deacetylate FOXO3a, in turn enhancing FOXO3a activity and increased expression of its targets, including antioxidant genes. In this way, SIRT3 protects mitochondria from oxidative stress [24]. Since SIRT3 actively modulate carbohydrate metabolism and ROS production, the role of SIRT3 in cancer metabolism has been highlighted [25]. Gius et al. first described that SIRT3 acts as a tumor suppressor by maintaining intact mitochondria in breast cancer [26]. Later, two studies provided mechanistic proof that HIF-1α (hypoxia inducible factor-1α) stabilization following mitochondrial ROS generation is critical to sustain cancer-prone metabolic reprogramming in SIRT3-deleted tumors [27,28].

SIRT3是一种主要的线粒体蛋白脱乙酰酶[17] ,调节多种代谢蛋白,如 TCA 循环蛋白异柠檬酸脱氢酶2(IDH2)[18]和电子转移链关键蛋白(ETC)[19-21]。在骨骼肌中,SIRT3在调节代谢适应性反应中起着重要作用。最近的研究表明,SIRT3对丙酮酸脱氢酶 e1α 的活性去乙酰化作用在营养胁迫条件下提供了代谢的灵活性。王和他的同事发现,SIRT3可以去乙酰化 FOXO3a,从而增强 FOXO3a 的活性,并增加其目标(包括抗氧化基因)的表达。通过这种方式,SIRT3保护线粒体免受氧化应激的伤害。由于 SIRT3主动调节糖代谢和活性氧的产生,SIRT3在癌症代谢中的作用已被强调[25]。Gius 等人首先描述 SIRT3作为一个肿瘤抑制因子保持完整的线粒体在乳腺癌[26]。随后,两项研究提供了机制性证据,证明缺氧诱导因子 -1α (hif-1α)在线粒体活性氧产生后的稳定性对于维持 sirt3缺失肿瘤的癌倾向代谢重编程至关重要[27,28]。

SIRT4 is mostly known for its role in glutamine metabolism. In proliferating cells, glutamine is the main source to replenish the TCA cycle as a source of α-ketoglutarate (α-KG) [29]. Two different groups recently reported new roles for SIRT4 in glutamine metabolism. Jeong et al. described that SIRT4 inhibits glutamine entry to the TCA cycle under genotoxic stress, preventing dysregulated proliferation and genomic instability [14]. Although SIRT4 appears to work by inhibiting GDH activity, how SIRT4 does so mechanistically remains to be fully understood. Notably, Csibi et al. found that the mTORC1-CREB2 axis can regulate SIRT4 transcription under various nutrient stress conditions, thereby affecting glutamine anaplerosis into the TCA cycle and cell proliferation [30], further confirming an important role for this sirtuin in glutamine metabolism.

SIRT4以其在谷氨酰胺代谢中的作用而闻名。在增殖细胞中,谷氨酰胺是补充 TCA 循环的主要来源,是 α- 酮戊二酸(α-kg)的来源[29]。最近有两个不同的组报道了 SIRT4在谷氨酰胺代谢中的新作用。Jeong 等人描述说,SIRT4抑制谷氨酰胺进入 TCA 周期在基因毒性应激,防止失调增殖和基因组不稳定[14]。虽然 SIRT4似乎是通过抑制 GDH 活性而发挥作用的,但 SIRT4是如何发挥作用的机制仍有待充分了解。值得注意的是,Csibi 等人发现 mTORC1-CREB2轴可以在各种营养胁迫条件下调节 SIRT4的转录,从而影响谷氨酰胺的分解进入 TCA 周期和细胞增殖[30] ,进一步证实了 sirtuin 在谷氨酰胺代谢中的重要作用。

SIRT5 has recently been defined as a lysine demalonylase and desuccinylase [31]. The global analysis of lysine succinylation (“succinylome”) in the context of SIRT5 demonstrated that this posttranslational modification has a regulatory effect on glucose metabolism by modulating the activities of PDH, SDH and mitochondrial respiration in mouse liver and MEFs [32]. The pioneering work of the Lin laboratory provided the first proof that sirtuins can work by removing non-acetyl acyl groups, defining sirtuins as “protein deacylases” and opening a whole new field in enzymology and biochemistry.

SIRT5最近被定义为赖氨酸脱核酶和脱核酶[31]。全球分析的赖氨酸琥珀酰化(“琥珀酰化”)的背景下,SIRT5表明,这一翻译后修饰有调节作用的葡萄糖代谢的活动,调节 PDH,SDH 和线粒体呼吸在小鼠肝脏和 MEFs [32]。林氏实验室的开创性工作首次证明了去乙酰化酶可以去除非乙酰酰基酰基,将去乙酰化酶定义为“蛋白质脱酰基酶” ,并开辟了酶学和生物化学的一个全新领域。

Previous work defined SIRT6 as a critical epigenetic regulator of glucose metabolism [33]. SIRT6 knockout (KO) mice exhibited a fatal hypoglycemic phenotype, which leads to death few weeks after birth [34]. The hypoglycemia resulted mainly from increased glucose uptake in muscle and brown adipose tissue. Mechanistically, SIRT6 negatively regulates HIF-1α-dependent transcription by deacetylating H3K9Ac at the promoter of several metabolic genes such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and PDH kinase 1 (PDHK1), thereby augmenting glucose uptake and glycolysis even under normoxia [35]. Such phenotype of aerobic glycolysis (also known as “Warburg effect” [36]), led to the hypothesis that SIRT6 could play a crucial role as a tumor suppressor. Indeed, ablation of SIRT6 enhanced tumor growth both in vitro and in vivo in models of colorectal cancer, [37]. More strikingly, treatment with the PDHK1 inhibitor dichloroacetate (DCA), reversed the tumorigenic phenotype in the context of SIRT6-deleted tumors, demonstrating that metabolic reprogramming is a driver of tumorigenesis. Two additional studies support the idea that SIRT6 acts as a tumor suppressor. Wagner and his colleagues reported that decreased level of SIRT6 plays a key role in AP-1-driven liver tumor by increasing H3K9Ac at the promoter of survivin and thus promoting cell survival [38]. This event is specific to tumor initiation, working in a c-Jun-dependent manner, thus implicating SIRT6 in liver tumor initiation. Another study reported that decreased level of SIRT6 is associated with poor clinical consequences in hepatocellular carcinoma (HCC) [39]. Taking into account that SIRT6 acts as well as a negative regulator of gluconeogenesis in liver via GCN5-dependent PGC-1α activation [40], it will be of particular interest to dissect how different metabolic outputs may contribute to liver tumorigenesis in a SIRT6 dependent manner.

先前的工作将 SIRT6定义为葡萄糖代谢的关键表观遗传调节因子[33]。SIRT6基因敲除(KO)小鼠表现出致命的低血糖表型,导致出生几周后死亡[34]。低血糖主要是由于肌肉和褐色脂肪组织中葡萄糖摄取增加所致。机制上,SIRT6通过在几个代谢基因如葡萄糖转运蛋白1(GLUT1)、乳酸脱氢酶 a (LDHA)和 PDH 激酶1(PDHK1)的启动子上去乙酰化 H3K9Ac 来负性调节 hif-1α 依赖性转录,从而增加葡萄糖摄取和糖酵解。这样的有氧糖酵解表型(也称为“ Warburg 效应”[36]) ,导致假设 SIRT6可以发挥关键作用,抑制肿瘤。事实上,在大肠癌模型中,SIRT6的消融在体内外都促进了肿瘤的生长。更引人注目的是,使用 PDHK1抑制剂二氯乙酸酯(DCA)治疗,可逆转 sirt6缺失肿瘤的致瘤表型,表明代谢重编程是肿瘤发生的驱动因素。另外两项研究支持 SIRT6作为肿瘤抑制基因的观点。Wagner 和他的同事报告说,SIRT6水平的降低在 ap-1驱动的肝肿瘤中起着关键作用,它可以增加 survivin 启动子上的 H3K9Ac,从而促进细胞存活[38]。这一事件是特定的肿瘤起始,工作在 c-jun 依赖的方式,因此牵连 SIRT6在肝脏肿瘤的起始。另一项研究报道,SIRT6水平的降低与不良的临床后果的肝细胞性肝癌(HCC)有关[39]。考虑到 SIRT6通过 gcn5依赖的 pgc-1α 激活作用以及肝脏糖异生的负调节因子[40] ,以 SIRT6依赖的方式研究不同的代谢输出如何促进肝脏肿瘤发生将特别有意义。

Lipid metabolism

脂质代谢

Lipids play fundamental roles as cellular membrane constituents and energy source, whose synthesis, storage, and expenditure are tightly regulated by different physiological cues, including fasting and nutrients availability. Excess nutrients from glucose, lipid and protein metabolism stimulate lipid synthesis, primarily in liver, in order to store energy inside white adipose tissue (WAT). Fatty acid (FA) synthesis occurs in the cytoplasm by using malonyl-CoA as an adaptor molecule and acetyl-CoA as a substrate of FA synthase (FAS), yielding acyl-CoA. On the other hand, FA oxidation happens in the mitochondrial matrix where β-oxidation produces acetyl-CoA, a key molecule in the TCA cycle to generate ATP. As energy/redox sensors, sirtuins actively modulate both FA synthesis and oxidation via transcriptional or posttranslational regulation [41]. Depending on the subcellular localization of sirtuins, they preferentially regulate either FA synthesis (cytoplasm) or FA oxidation (mitochondria).

脂类作为细胞膜成分和能量来源扮演着基本的角色,其合成、储存和消耗都受到不同生理线索的严格调节,包括禁食和营养物质的可用性。来自葡萄糖、脂肪和蛋白质代谢的过量营养物质刺激脂质合成,主要是在肝脏,以便在白色脂肪组织中储存能量。脂肪酸(FA)是以丙二酰辅酶 a 为接头分子,乙酰辅酶 a 为脂肪酸合成酶(FAS)底物,产生酰辅酶 a 而在细胞质中合成的。另一方面,FA 氧化发生在线粒体基质中,β 氧化产生乙酰辅酶 a,这是 TCA 循环中产生 ATP 的关键分子。作为能量/氧化还原传感器,sirtuins 通过转录或翻译后调节活跃地调节 FA 的合成和氧化[41]。根据去乙酰化酶的亚细胞定位,它们优先调节 FA 合成(细胞质)或 FA 氧化(线粒体)。

SIRT1 deacetylates and suppresses sterol-response element-binding protein 1c (SREBP1c)-dependent transcription, targeting triglyceride synthesis in the liver [42,43]. SIRT1 also plays a key role in hepatic FA utilization during fasting [44] or HFD [45], mediating the transcriptional activation of PPARα/PGC-1α-dependent genes. Li and his group further demonstrated that liver-specific genetic ablation of SIRT1 caused hepatic steatosis in vivo [46]. In skeletal muscle, a SIRT1/PGC-1α complex is activated via cAMP/PKA signaling cascade from adrenergic stimuli to increase FA oxidation [47]. Interestingly, oleic acid among long-chain free FA (LCFFA) specifically stimulates FA utilization in skeletal muscle through a PKA-SIRT1-PGC-1α pathway [48], suggesting that a single LCFFA evolved the capability to regulate FA metabolism. Whether this represents a highly specialized feedback mechanism and the physiological relevance of these effects remain to be determined.

SIRT1去乙酰化并抑制甾醇反应元件结合蛋白1c (SREBP1c)依赖的转录,靶向肝脏中甘油三酯的合成[42,43]。SIRT1还在禁食期间肝脏 FA 的利用中发挥关键作用,介导 PPARα/PGC-1 α 依赖基因的转录激活。Li 和他的团队进一步证明了 SIRT1的肝特异性基因消融在体内引起了肝脏脂肪变性[46]。在骨骼肌中,SIRT1/PGC-1α 复合物通过肾上腺素能刺激的 cAMP/PKA 信号级联被激活,从而增加 FA 氧化[47]。有趣的是,长链游离脂肪酸(LCFFA)中的油酸通过 pka-sirt1-pgc-1α 途径特异性地刺激骨骼肌对 FA 的利用,提示单个 LCFFA 进化出了调节 FA 代谢的能力。这是否代表一个高度专门化的反馈机制和这些影响的生理相关性仍有待确定。

SIRT3 and SIRT4 play as well important roles in FA oxidation. Genetic ablation of SIRT3 alters acetylation status of several metabolic enzymes including long-chain acyl-CoA dehydrogenase (LCAD), decreasing FA oxidation in liver mitochondria [49] and predisposing to metabolic syndrome [50]. Recently, the precise lysine sites in LCAD targeted by SIRT3 (K318/K322) were identified [51]. Given that hundreds of mitochondrial proteins are hyperacetylated in SIRT3−/− mitochondria, future work will be required to fully grasp the functional and physiological consequences of such modifications. Although SIRT4 has been known to regulate FA oxidation in liver and skeletal muscle [52], only recently we learned SIRT4 as a repressor of malonyl-CoA decarboxylase (MCD) [53]. MCD is a core enzyme to balance the levels of malonyl-CoA and acetyl-CoA in mitochondria, and thus it is a key module of lipid anabolism and catabolism. Through deacetylation and inhibition of MCD activity, SIRT4 favors FA synthesis over FA oxidation in fed condition and deletion of SIRT4 has a protective role in HFD-induced obesity.

SIRT3和 SIRT4在 FA 氧化过程中起着重要作用。SIRT3的基因消融改变了几种代谢酶的乙酰化状态,包括长链酰基辅酶 a 脱氢酶(LCAD) ,降低肝线粒体的 FA 氧化和易感代谢症候群。最近,SIRT3(K318/K322)在 LCAD 中精确的赖氨酸位点被鉴定[51]。鉴于 SIRT3-/-线粒体中有数以百计的线粒体蛋白质被过度乙酰化,未来的工作将需要充分掌握这种修饰的功能和生理后果。虽然 SIRT4已知可以调节肝脏和骨骼肌的 FA 氧化,但是我们最近才知道 SIRT4是一种丙二酰辅酶A脱羧酶的抑制剂。MCD 是平衡线粒体中丙二酰辅酶 a 和乙酰辅酶 a 水平的核心酶,是脂质合成和分解代谢的关键模块。SIRT4通过去乙酰化和抑制 MCD 活性,促进脂肪酸的合成而不是脂肪酸的氧化,SIRT4的缺失对 hfd 诱导的肥胖有保护作用。

SIRT6 KO mice presents complete loss of subcutaneous fat in addition to its hypoglycemic phenotype, indicating a potential role for SIRT6 in lipid metabolism [34]. Indeed, Kim et al. observed that liver-specific deletion of SIRT6 facilitates fatty liver formation by increasing triglyceride (TG) synthesis [54]. SIRT6 represses transcription of lipid metabolism-related genes including acetyl-CoA carboxylase (ACC) and FAS by H3K9 deacetylation. Recently, SIRT6 role in lipid metabolism was further investigated as a regulator of LDL (low-density lipoprotein) and cholesterol [55,56]. SIRT6 form a complex with FOXO3a, regulating H3K9Ac and H3K56Ac levels in the promoter of the Pcsk9 (proprotein convertase subtilisin/kexin type 9) gene, in turn repressing LDLR (LDL receptor) expression, an important membrane receptor for LDL and cholesterol internalization in liver [55]. Notably, SIRT6 overexpressing mice exhibited protective effect from HFD-induced LDL and cholesterol increase in the blood. In a separate study, the same group also reported that SREBP-2 is another key regulator in cholesterol homeostasis in a FOXO3/SIRT6-dependent manner [56]. Using one of the first models of SIRT6 overexpression, Cohen and his colleagues deciphered further mechanistic insights on SIRT6 regulating SREBP-1/2 in liver [57], following their original study demonstrating extension of lifespan in SIRT6 transgenic mice [58]. In addition to transcriptional repression of SREBP-1/2, SIRT6 modulates SREBP-1/2 by proteolytic cleavage and phosphorylation of SREBP-1 via activation of AMPK (AMP kinase). In a reciprocal manner, the microRNAs miR33a and miR33b, expressed from the introns of SREBP-2 and -1 respectively, down-regulate SIRT6 level. Such roles for SIRT6 explained the protection against hypercholesterolemia following HFD treatment in SIRT6 transgenic mice. These studies provide multi-layered regulation of lipid metabolism by SIRT6, confirming a critical role for SIRT6 in lipid metabolism and metabolic syndrome related disorders.

除了低血糖表型外,SIRT6 KO 小鼠完全丧失了皮下脂肪,这表明了 SIRT6在脂质代谢中的潜在作用[34]。实际上,Kim 等人观察到 SIRT6肝特异性缺失通过增加甘油三酯(TG)合成促进脂肪肝的形成[54]。SIRT6通过 H3K9去乙酰化抑制脂代谢相关基因包括乙酰辅酶A羧化酶和脂肪酸合成酶的转录。最近,SIRT6在脂质代谢中的作用被进一步研究为低密度脂蛋白(低密度脂蛋白)和胆固醇的调节剂[55,56]。SIRT6与 FOXO3a 形成复合物,调节 Pcsk9(proprotein convertase subtilisin/kexin type 9)基因启动子中 H3K9Ac 和 H3K56Ac 的水平,进而抑制 LDLR (LDL 受体)的表达,这是低密度脂蛋白胆固醇和肝脏内在化的重要细胞表面受体。值得注意的是,SIRT6过度表达的小鼠表现出保护作用,从高密度脂蛋白诱导的低密度脂蛋白和胆固醇增加的血液。在另一项单独的研究中,同一研究小组还报道,SREBP-2是另一个以 foxo3/sirt6依赖方式影响胆固醇稳态的关键调节因子[56]。利用第一批 SIRT6过度表达的模型之一,Cohen 和他的同事们进一步阐明了 SIRT6调节肝脏 SREBP-1/2的机制,他们的原始研究证明了 SIRT6转基因小鼠寿命的延长[58]。SIRT6除了通过对 SREBP-1/2的转录抑制外,还通过蛋白水解和磷酸化活化 AMPK 来调节 SREBP-1/2。微小 rna miR33a 和 miR33b 分别从 SREBP-2和-1的内含子表达,以相互作用的方式下调 SIRT6水平。6的这些作用解释了 SIRT6转基因小鼠在 HFD 治疗后对高胆固醇血症的保护作用。这些研究提供了 SIRT6对脂质代谢的多层次调节,证实了 SIRT6在脂质代谢和代谢症候群相关疾病中的关键作用。

Surprisingly, SIRT6 has shown very weak in vitro deacetylase activity, making biochemical analysis challenging. This in vitro observation led to two possible hypotheses: one was that SIRT6 needs a certain biological context to fully act as a deacetylase. The other postulated a novel enzymatic activity. Astonishingly, it appears that both hypotheses were right. Similar to the desuccinylase and demalonylase activity defined for SIRT5 [31], the same group demonstrated that SIRT6 possesses a novel enzymatic activity as a LCFA deacylase, working as demyristoylase and depalmitoylase in vitro [59]. Supported by in vivo results, the study found that SIRT6 demyristoylate TNFα, stimulating its secretion in macrophages. On the other hand, Denu and colleagues discovered that in vitro SIRT6 deacetylase activity is stimulated a thousand fold by free FA (FFA), performing as robust as any of the other sirtuins [60]. This study provided a unique biochemical basis to define a novel regulatory loop, where FFAs in cells can act as allosteric regulators to stimulate SIRT6 activity, which in turn will tune FA metabolism to bring back homeostasis.

令人惊讶的是,SIRT6在体外的去乙酰化酶活性非常弱,使生化分析具有挑战性。这种体外观察导致了两种可能的假设: 一是 SIRT6需要一定的生物环境才能充分发挥脱乙酰基酶的作用。另一个假设了一种新的酶活性。令人惊讶的是,这两种假设似乎都是正确的。与 SIRT5[31]所定义的脱核酶和脱核酶活性相似,同一基因组也证明 SIRT6具有一种新的酶活性,即 LCFA 脱酰酶,在体外作用于脱肉豆蔻酰酶和脱核酶[59]。在体内实验结果的支持下,研究发现 SIRT6能够促进巨噬细胞分泌肿瘤坏死因子 α。另一方面,Denu 和他的同事们发现,在体外 SIRT6脱乙酰基酶的活性受到游离脂肪酸(FFA)的千倍刺激,表现得和其他去乙酰化酶一样强健[60]。这项研究提供了一个独特的生化基础,以确定一个新的调节环,其中在细胞中的游离脂肪酸可以作为变构调节剂刺激 SIRT6活性,这反过来将调节 FA 代谢带回稳态。

Although much less is known about SIRT7, a recent study showed that it alleviates HFD-induced hepatosteatosis by co-repressing Myc transcriptional activity and thus decreasing ER stress in liver [61]. In vivo genetic ablation and overexpression of SIRT7 confirmed that this protective effect of SIRT7 is Myc-dependent. Although a previous study defined SIRT7 as an H3K18 deacetylase [62], future investigations will uncover by which mechanism(s) SIRT7 regulates Myc-dependent transcription in lipid metabolism.

虽然对 SIRT7的了解还很少,但最近的一项研究表明,它通过共同抑制 Myc 转录活性,从而减少肝脏内质网应激,从而减轻了 hfd 诱导的肝脏骨质形成。体内基因消融和 SIRT7的过表达证实了 SIRT7的保护作用与 myc 有关。虽然先前的研究将 SIRT7定义为 H3K18脱乙酰基酶[62] ,但是未来的研究将揭示 SIRT7调节脂质代谢 myc 依赖性转录的机制。

NAD+ and Metabolism

和新陈代谢

It has long been postulated that modulation of NAD levels could serve as a mean to regulate sirtuin activity, influencing metabolism. A first proof for such hypothesis came from work by the Imai lab, where they showed that treatment of mice with the NAD precursor nicotinamide mononucleotide (NMN) ameliorated glucose intolerance and diabetes in both HFD-treated and aged animals [63]. Such effects were partly dependent on SIRT1. Supporting these studies, recent work demonstrated that supplementation with another NAD+ precursor, nicotinamide riboside (NR), increases intracellular and mitochondrial NAD+ levels, thus activating SIRT1 and SIRT3, and subsequently enhancing oxidative metabolism both in vitroand in vivo [64]. This study also showed that NR supplementation protected against HFD-induced obesity. Remarkably, Sinclair and colleagues discovered that nuclear NAD+ levels affect SIRT1 activity to regulate mitochondrial OXPHOS and overall homeostasis in mice [65]. When nuclear NAD+ levels are significantly reduced, as seen with aging, SIRT1 activity is compromised and mitochondrial metabolism is severely impaired through HIF-1α-, c-Myc- and PGC-1α-mediated mechanisms, causing a pseudohypoxic state. Furthermore, interventions to increase NAD+ levels by calorie restriction and supplementation with NMN partially restored mitochondrial homeostasis and metabolism, further defining NAD+ as a key modulatory factor in metabolism-associated aging phenotypes. Even though all these studies provided evidence to support a role for SIRT1 and SIRT3 downstream of NAD availability, whether other sirtuins may as well being involved in those phenotypes remains to be established.

长期以来,人们一直认为 NAD 水平的调节可以作为调节去乙酰化酶活性,影响新陈代谢的一种手段。这种假设的第一个证据来自 Imai 实验室的工作,他们表明,用 NAD 前体尼古丁酰胺单核苷酸(NMN)治疗小鼠可以改善被 hfd 治疗和老年动物的葡萄糖耐受不良和糖尿病[63]。这种影响部分依赖于 SIRT1。支持这些研究,最近的工作表明,补充另一种 NAD + 前体,烟酰胺核苷(NR) ,增加细胞内和线粒体 NAD + 水平,从而激活 SIRT1和 SIRT3,并随后在体外和体内增强唿吸作用。本研究还表明补充硝酸还原酶对高频血糖诱导的肥胖有保护作用。值得注意的是,辛克莱和他的同事发现,核 NAD + 水平影响 SIRT1调节线粒体 OXPHOS 和小鼠整体内稳态的活性[65]。随着年龄的增长,当 NAD + 核水平显著降低时,SIRT1活性受损,线粒体代谢通过 hif-1α-、 c-Myc-和 pgc-1α 介导的机制严重受损,导致假缺氧状态。此外,通过卡路里限制和补充 NMN 提高 NAD + 水平的干预措施部分恢复了线粒体内环境稳定和新陈代谢,进一步明确了 NAD + 作为新陈代谢相关表型的关键调节因子。尽管所有这些研究都为 SIRT1和 SIRT3在 NAD 可用性下游的作用提供了证据,但其他去乙酰化酶是否也可能参与这些表型还有待确定。Go to: 去:

Sirtuins in DNA repair

DNA 修复中的去乙酰化酶

Our cells are constantly exposed to genomic insults and four major pathways evolved in eukaryotes to resolve DNA damage; homologous recombination (HR), non-homologous end joining (NHEJ), base-excision repair (BER), and nucleotide-excision repair (NER) [66]. For single-strand breaks (SSB), BER and NER are major repair mechanisms to repair the nucleotides using the sister strand as a template. ROS-mediated SSBs preferentially undergoes BER repair, while bulky adducts and UV-induced thymidine dimers are prone to be repaired by NER. For double-strand breaks (DSB), more detrimental to the genome, cells choose either HR or NHEJ to repair the damaged DNA. If cells find a homologous DNA region from a sister chromatid in proximity to the DNA damage, HR serves as a repair mechanism to rebuild the whole damaged area using the template chromatid (indeed, HR is the dominant repair pathway during S phase). In contrast, in non-dividing cells, ligation of two damaged DNA ends with little homology occurs via NHEJ, an error-prone DDR pathway. Notably, sirtuins have evolved to modulate multiple repair pathways. As explained in detail below, some of them modulates activity of DNA repair factors through deacetylation, others influence chromatin accessibility to enhance recruitment of repair factors, while others influence repair by preventing DNA damage indirectly, by means of modulating the cell cycle and preventing oxidative stress.

我们的细胞不断地暴露在基因组的损伤中,真核生物进化出了4条主要途径来解决 DNA 损伤: 同源重组(HR)、非同源性末端接合(NHEJ)、碱基切除修复(BER)和核苷酸切除修复(NER)[66]。对于单链断裂(SSB) ,BER 和 NER 是以姐妹链为模板修复核苷酸的主要修复机制。Ros 介导的 ssb 优先进行 BER 修复,而较大的加成物和紫外线诱导的胸腺嘧啶二聚体容易被 NER 修复。对于双链断裂(DSB) ,更有害的基因组,细胞选择 HR 或 NHEJ 修复受损的 DNA。如果细胞在 DNA 损伤附近发现一个来自姐妹染色单体的同源 DNA 区域,HR 作为一种修复机制,利用模板染色单体重建整个损伤区域(事实上,在 s 期 HR 是主要的修复途径)。相比之下,在非分裂细胞中,连接两个损伤的 DNA 末端几乎没有同源性,这是一个容易出错的 DDR 通路。值得注意的是,去乙酰化酶已经进化成可以调节多种修复途径。正如下面详细解释的,其中一些通过脱乙酰基调节 DNA 修复因子的活性,其他影响染色质的可及性,以增加修复因子的招募,而其他影响修复通过间接防止 DNA 损伤,通过调节细胞周期和防止氧化应激。

SIRT1

SIRT1 null mice present embryonic lethality mainly due to impaired DDR and chromosomal abnormalities [67]. Indeed, SIRT1 regulates the activity of several proteins important for HR repair, such as NBS1 [68], Rad51 [69], and the DSB sensing protein WRN [70]. Recent studies show that SIRT1 also regulates NHEJ via cooperative action with ATM and HDAC1 in postmitotic neurons [71]. On one hand, SIRT1 sustains prolonged activity of ATM, and on the other hand, it also stimulates HDAC1 activity by deacetylating this enzyme at sites of DSBs. SIRT1 also plays key roles in NER via deacetylation and recruitment of XPA [72] and XPC [73] (Xeroderma Pigmentosum A and C) to the sites of damage. All together, these results indicate that SIRT1 evolved to perform multiple functions in different DNA repair pathways, highlighting its critical role in protecting against genomic instability.

SIRT1缺失小鼠的胚胎致死率主要是由于 DDR 受损和染色体异常[67]。事实上,SIRT1控制着几种对 HR 修复非常重要的蛋白质的活性,比如 NBS1[68] ,Rad51[69] ,和 DSB 感应蛋白 WRN [70]。最近的研究表明 SIRT1也通过与 ATM 和 HDAC1在有丝分裂后神经元的协同作用来调节 NHEJ。一方面,SIRT1维持了 ATM 的长期活性,另一方面,它也通过在 dsb 位点去乙酰化这种酶来刺激 HDAC1的活性。SIRT1还通过 XPA [72]和 XPC [73](着色性干皮症 a 和 c)的脱乙酰化和补充在 NER 中发挥关键作用。综上所述,这些结果表明 SIRT1在不同的 DNA 修复途径中发挥多种功能,突出了其在保护基因组不稳定性方面的关键作用。

SIRT2

Initial studies demonstrated a potential role for SIRT2 in cell cycle progression, especially during mitosis, given that levels of SIRT2 drastically varies throughout the cell cycle [74]. Recently, two studies highlighted novel roles for SIRT2 in replication stress and genomic integrity [75,76]. The replication stress response (RSR) is one of the DDR signaling pathways to keep genome integrity. SIRT2 can relieve RS through deacetylation and activation of CDK9 [75]. Vaquero and his group discovered that deacetylation of H4K16Ac by SIRT2 facilitates H4K20 methylation by the PR-Set7 methyltransferase, regulating mitotic entrance [76]. Notably, loss of SIRT2 facilitated tumor formation in a model of skin squamous cell carcinoma [76], indicating a potential role for SIRT2 in protecting against genomic instability, thereby preventing tumorigenesis.

最初的研究证明了 SIRT2在细胞周期进程中的潜在作用,特别是在有丝分裂期间,因为 SIRT2的水平在整个细胞周期中发生了巨大的变化[74]。最近,两项研究强调了 SIRT2在复制应激和基因组完整性方面的新作用[75,76]。复制应激反应(RSR)是维持基因组完整性的 DDR 信号通路之一。SIRT2可通过去乙酰化和激活 CDK9来缓解 RS。和他的团队发现 SIRT2对 H4K16Ac 的去乙酰化促进了 PR-Set7甲基转移酶的 H4K20甲基化,从而调节有丝分裂入口[76]。值得注意的是,SIRT2的缺失促进了皮肤鳞状细胞癌模型中的肿瘤形成[76] ,这表明 SIRT2在保护基因组不稳定性方面的潜在作用,从而阻止了肿瘤的发生。

Mitochondrial sirtuins

线粒体去乙酰化酶

Considering their exclusive localization in the mitochondria, it is reasonable to think that SIRT3, 4 and 5 play no direct role on nuclear DNA repair. However, they are of critical importance to prevent accumulation of mitochondrial ROS (reactive oxygen species) in turn preventing DNA damage. Kim et al. first demonstrated that SIRT3 deletion leads to an increased level of superoxide and genomic instability under stress conditions, enhancing tumor development in mammary glands [25]. Several groups showed that high ROS level results from failure to activate SOD2 (MnSOD, manganese superoxide dismutase) via deacetylation by SIRT3 [7779]. SIRT3 also regulates glutathione-mediated redox balance [18] and ROS generation from complex III [26], further supporting a protective role for SIRT3 against oxidative stress. As mentioned above, SIRT4 levels are increased by DNA damage, acting as a glutamine gatekeeper to regulate anaplerosis towards the TCA cycle, coordinating DDR and metabolism [14]. SIRT4 reduces entrance of glutamine to the TCA cycle by reducing glutamate dehydrogenase (GDH) activity. Inhibition of glutamine metabolism causes cells to arrest, providing sufficient time for these cells to repair DNA. Cells lacking SIRT4 continue to proliferate unabated following DNA damage, in turn accumulating genomic instability. In this context, SIRT4 acts as a tumor suppressor in models of breast and lung cancer [13,29].

鉴于 SIRT3、4和5在线粒体中的独特定位,可以认为它们在细胞核 DNA 修复中没有直接作用。然而,它们对于防止线粒体内 ROS (活性氧类)的积累从而防止 DNA 损伤至关重要。Kim 等人首先证明了 SIRT3缺失导致在应激条件下超氧化物水平和基因组不稳定性增加,促进了乳腺肿瘤的发展[25]。有几组研究表明,高水平的活性氧是由于 SIRT3[77-79]不能通过脱乙酰作用激活 SOD2(MnSOD,锰超氧化物歧化酶)而引起的。SIRT3还调节谷胱甘肽介导的氧化还原平衡[18]和复合物 III 产生活性氧,进一步支持 SIRT3对氧化应激的保护作用。正如上面提到的,SIRT4水平由于 DNA 损伤而增加,作为一个谷氨酰胺守门人来调节 TCA 循环的回指,协调 DDR 和新陈代谢[14]。SIRT4通过降低谷氨酰胺(GDH)活性减少谷氨酰胺进入 TCA 循环。谷氨酰胺代谢的抑制导致细胞停滞,为这些细胞修复 DNA 提供足够的时间。缺乏 SIRT4的细胞继续增殖有增无减的 DNA 损伤,反过来积累基因组的不稳定性。在这种情况下,SIRT4在乳腺癌和肺癌模型中起抑癌作用[13,29]。

SIRT6

Extensive studies cemented a role for SIRT6 in numerous DNA repair pathways. SIRT6 KO cells exhibit hypersensitivity to genotoxic agents and genomic instability [33]. In that original study, SIRT6 was proposed to work on BER, by mechanisms that remain poorly understood. Chua and her group first illustrated that SIRT6 is necessary for efficient DNA DSB repair as well, mainly by stabilizing DNA-PK (DNA-dependent protein kinase) at DSB sites in turn promoting NHEJ repair [80]. Moreover, SIRT6 protects telomeric chromatin from DNA damage and genomic instability, acting as an H3K9 and H3K56 deacetylase [12,81]. Deacetylation of H3K9 by SIRT6 promotes the stable association of the WRN protein at telomere regions, important for processing telomeres in S phase [12]. Another study found CtIP (CtBP interacting protein) as a novel substrate of SIRT6, which facilitates the resection of the DSBs and DNA repair by HR [82]. PARP1 (poly-[adenosine diphosphate (ADP)–ribose] polymerase 1) is the first target for mono- ADP ribosylation by SIRT6, resulting in enhanced DSB repair both by NHEJ and HR specifically following oxidative stress [83]. Interestingly, a recent study found that chromatin remodeling by SIRT6 also plays a crucial role in DSB repair [84]. SIRT6 is recruited to sites of DSBs, recruiting SNF2h, an ATP-dependent chromatin remodeler, to open chromatin, providing proper docking sites for further recruitment of downstream DDR factors, allowing efficient repair. This study is particularly meaningful, providing in vivo data that SIRT6 is critical for SNF2h recruitment to chromatin following DDR in brain and pancreas. Taken together, all these studies demonstrate that SIRT6 plays multiple roles at different layers during DNA repair. How such roles are coordinated, and what are the unique determinants that modulate specificity, remain yet to be discovered.

广泛的研究巩固了 SIRT6在众多 DNA 修复途径中的作用。SIRT6 KO 细胞表现出对基因毒剂和基因组不稳定的过敏。在那个原始的研究中,SIRT6被提议用于研究 BER,其机制仍然知之甚少。Chua 和她的研究小组首先阐明了 SIRT6对 DNA DSB 的有效修复也是必要的,主要是通过稳定 DNA 依赖性蛋白激酶(DNA-dependent protein kinase,DNA-pk)在 DSB 位点,反过来促进 NHEJ 修复[80]。此外,SIRT6保护端粒染色质免受 DNA 损伤和基因组不稳定,作为一个 H3K9和 H3K56脱乙酰基酶[12,81]。SIRT6对 H3K9的脱乙酰化促进了 WRN 蛋白在端粒区域的稳定结合,这对于端粒 s 期的处理非常重要。另一项研究发现 CtIP (CtBP 相互作用蛋白)作为 SIRT6的一种新的底物,可以促进 dsb 的切除和 HR [82]的 DNA 修复。PARP1(poly-[二磷酸腺苷(ADP)-核糖]聚合酶1)是 SIRT6单 ADP 核糖基化的第一个靶点,导致 NHEJ 和 HR 特异性地在氧化应激后增强 DSB 修复[83]。有趣的是,最近的一项研究发现,SIRT6的染色质重塑在 DSB 修复中也起着关键作用。SIRT6被招募到 dsb 的位点,招募一个 atp 依赖的染色质重塑基因 SNF2h 来开放染色质,为进一步招募下游的 DDR 因子提供适当的对接位点,从而允许有效的修复。这项研究特别有意义,它提供了 SIRT6在大脑和胰腺 DDR 后 SNF2h 补充到染色质中至关重要的活体数据。综上所述,所有这些研究都表明,SIRT6在 DNA 修复的不同层次发挥着多种作用。这些角色是如何协调的,以及调节特异性的独特决定因素是什么,仍有待发现。Go to: 去:

Concluding remarks: the metabolism-DNA repair connection

结束语: 新陈代谢-dna 修复连接

Considering that the repair of DNA needs energy as well as particular metabolic intermediates for signaling, cells may have evolved specific mechanistic crosstalks to coordinate metabolic activities for efficient DNA repair responses. As we discussed above, sirtuins play significant roles both in metabolism and DNA repair, implicating that sirtuins may work as a hub to coordinate these two seemingly different cellular processes. One interesting perspective is that metabolic intermediates are necessary for a series of enzymatic functions in DDR. Indeed, several enzymes in DDR are regulated by sirtuin-dependent acetylation/deacetylation, such as NBS1 [68] and WRN [70]. Given that acetyl-CoA is necessary for acetylation of proteins, and NAD+ is a cofactor of both sirtuins and the DNA repair factor PARP, one could argue that changes in availability of acetyl-CoA and NAD+ could play critical limiting steps for proper DDR. Further, given the role of chromatin dynamics in DNA repair, changes in chromatin structure that depends on histone acetylation and methylation could directly impinge on efficient DNA repair. Therefore, we could infer that availability of acetyl-coA and methyl groups from one-carbon metabolism could directly influence genetic stability. Although such scenarios have recently been elegantly discussed from a theoretical point of view [85,86], such hypotheses remain to be experimentally tested. Given the extensive roles (discussed above) in both metabolism and DNA repair, sirtuins could be coordinating such efforts. For example, DNA damage-dependent increase in SIRT4 dampens glutamine metabolism, providing a proliferation checkpoint to ensure proper DNA repair, as implicated in Jeong et al. [14]. The recent findings defining activation of SIRT6 by FFA [60], suggest that limiting availability of acetyl-CoA could determine levels of FFA in cells, in turn modulating SIRT6 activity. SIRT6 regulates, at the transcriptional level, genes involved in lipolysis, while at the same time influences DNA repair through its deacetylase activity. Finally, acetyl-groups removed from histones in the nucleus could be shuffle back into the cellular pools to restore metabolic balance [85]. While such crosstalks are debated in a theoretical arena, active research in these areas is likely to provide experimental evidence in the near future.

考虑到 DNA 的修复需要能量以及特定的信号代谢中间物,细胞可能已经进化出特定的机械交叉作用来协调 DNA 修复反应的代谢活动。正如我们上面所讨论的,去乙酰化酶在新陈代谢和 DNA 修复中都扮演着重要的角色,这暗示着去乙酰化酶可以作为一个枢纽协调这两个看似不同的细胞过程。一个有趣的观点是,代谢中间物是必要的一系列酶的功能在 DDR。事实上,一些在 DDR 中的酶是由 sirtuin 依赖的乙酰化/去乙酰化调节的,例如 NBS1[68]和 WRN [70]。鉴于乙酰辅酶 a 对蛋白质的乙酰化是必要的,而 NAD + 是去乙酰化酶和 DNA 修复因子 PARP 的辅助因子,人们可以认为乙酰辅酶 a 和 NAD + 的可利用性的改变可以发挥关键的限制步骤适当的 DDR。此外,鉴于染色质动力学在 DNA 修复中的作用,依赖于组蛋白乙酰化和甲基化的染色质结构变化可能直接影响 DNA 的有效修复。因此,我们推断乙酰辅酶 a 和甲基在单碳代谢中的有效性直接影响遗传稳定性。虽然这些假设最近已经从理论的角度得到了很好的讨论,但是这些假设还有待于实验验证。鉴于在新陈代谢和 DNA 修复中的广泛作用(上面已经讨论过) ,去乙酰化酶可以协调这些努力。例如,DNA 损伤依赖性增加的 SIRT4抑制谷氨酰胺代谢,提供一个增殖检查点,以确保适当的 DNA 修复,牵连在 Jeong 等人[14]。最近的发现定义激活 SIRT6的 FFA [60] ,表明限制可用性乙酰辅酶 a 可以确定水平的 FFA 细胞,反过来调节 SIRT6的活性。SIRT6在转录水平上调节与脂解有关的基因,同时通过其去乙酰化酶活性影响 DNA 修复。最后,从细胞核中组蛋白去除的乙酰基团可以被洗牌回到细胞池中恢复新陈代谢平衡。虽然这样的串音在理论上存在争议,但在这些领域的积极研究很可能在不久的将来提供实验证据。​

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Figure 1 图1Sirtuins functions in metabolism and DNA repair 去乙酰化酶在代谢和 DNA 修复中的作用

A diagram depicting the different functions for the mammalian sirtuins in cellular metabolism (red) and DNA repair (blue). Specific targets and biological roles are summarized.

图解描绘了哺乳动物去乙酰化酶在细胞代谢(红色)和 DNA 修复(蓝色)中的不同功能。概述了其具体目标和生物学作用。Go to: 去:

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