Mol Cell Biochem (2012) 364:345350 DOI 10.

1007/s11010-012-1236-8

Emerging roles of SIRT6 on telomere maintenance, DNA repair, metabolism and mammalian aging
Gaoxiang Jia Ling Su Sunil Singhal Xiangguo Liu

Received: 1 November 2011 / Accepted: 13 January 2012 / Published online: 29 January 2012 Springer Science+Business Media, LLC. 2012

Abstract With the characterization of Sir2 gene in yeast aging, its mammalian homologs Sirtuins 17 have been attracting attention from scientists with various research backgrounds. Among Sirtuins, SIRT1 is the most extensively studied. Recent progress on mammalian Sirtuins has shown that SIRT6 as a histone deacetylase may also play a critical role in regulating mammalian aging. This review summarizes recent advances on SIRT6 as a key modulator of telomere structure, DNA repair, metabolism, and NFkappa B pathway in aging. In addition, we discuss the challenges that remain to be studied in SIRT6 biology. Keywords SIRT6 Telomere structure DNA repair Metabolism Mammalian aging

The Sirtuin protein family is the mammalian homolog of yeast Sir2 which contains 7 members (Sirtuins 17) [13]. In 1997, Sinclair and Guarente [4] showed the accumulation of extrachromosomal rDNA circles (ERCs) due to homologous recombination between rDNA repeated sequences leads to yeast aging. Two years later, Kaeberlein et al. [5] discovered Sir2 represses the recombination between rDNA repeated sequences, decreases the production and accumulation of ERCs, and thus prolongs the life span of yeast. Since then,
G. Jia L. Su X. Liu (&) Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, South Building, Room 103, 27 Shanda South Road, Jinan 250100, Peoples Republic of China e-mail: xgliu@sdu.edu.cn S. Singhal Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA

mammalian homologs of Sir2-Sirtuins have become the highlight of aging biology research. To date, Sirtuins have not been shown to regulate the mammalian life span directly. However, the Sirtuins family members have been shown to need NAD? as a co-substrate when activated indicating their pivotal roles in sensing the energetic state of cells during metabolism and thus may affect mammalian aging through calorie restriction (CR) [1]. Since Sir2s role in aging was discovered, extensive research has been done on SIRT1-mammalian homolog of Sir2. However, the abnormal phenotype of SIRT6 knockout mice indicates SIRT6 is also critical for a set of physiological processes. When compared with normal mice, SIRT6 decient mice are much smaller and develop a series of deciencies including loss of subcutaneous fat, signicant decrease of lymphocytes, lordokyphosis, and severe metabolic disorders by 23 weeks of age, and typically die within 4 weeks [6]. An emerging role of SIRT6 on telomere maintenance, DNA repair, and mammalian aging has been indicated by further in-depth research at the molecular level. Thus, this review summarizes recent progresses of SIRT6 study on telomere maintenance, DNA repair, and mammalian aging and discusses the remaining questions that are being posed with regards to the function and activity of SIRT6.

SIRT6 can regulate telomere structure Telomeres are long repeated sequences located on the terminal regions of eukaryotic chromosomes which were rst identied by Barbara Mclintock in Zea mays [79]. By existing in a highly condensed chromatin state known as heterochromatin, telomeres can prevent genetic information loss caused by the inability of DNA polymerase to

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replicate the end of chromosomes [10]. In addition, telomeres protect the chromosomes from end fusion which is the main cause of breakage-fusion-bridge cycle, thus preventing the occurrence of genome instability [11, 12]. Sufcient evidence shows that telomere dysfunction may trigger tumor formation which underlines the important role of telomeres in maintaining the genome [1215]. In somatic cells, due to the inactivation of telomerase, telomeres shorten with each replication cycle. In 1992, Allsopp et al. [16] found the length of telomeres could be used to predict the replicative potential of human broblasts, indicating its role as a biomarker of cellular senescence which results from shortening of telomeres. SIRT6 mainly resides in the nucleus as a chromatin binding protein [17]. In 2008, Michishita et al. [18] showed that SIRT6 as a NAD? dependent histone H3 lysine 9 (H3K9) deacetylase can modulate telomeric chromatin structure. SIRT6 can specically bind to the telomeric chromatin and its loss can lead to the dysfunction of telomeres which further results in chromosome end fusion with cellular senescence. SIRT6 knockdown experiments indicated a phenotype of telomere abnormality similar to that of Werner syndrome [1820]. Subsequent experiments showed that SIRT6 specically deacetylates H3K9 and prevents the tight binding of WRN (mutated in individuals with Werner syndrome) to the telomere. This is likely due to deacetylation which condenses the telomeres due to the neutralization of opposite charges between the DNA and histones [18, 21]. Thus, the mechanism of SIRT6 on modulating telomere structure and affecting cellular senescence is the same as WRN. In 2009, Michishita et al. [22] reported SIRT6 can dynamically regulate the acetylation level of H3K56 under cell cycle arrest. Its functions are still being studied. To date, only H3K9 and H3K56 have been reported to be the deacetylation target of SIRT6.

SIRT6 promotes DNA repair In 2006, Mostoslavsky et al. identied SIRT6 decient mouse embryonic broblasts (MEFs) and stem cells are more sensitive to DNA damaging agents and replicate slower than normal cells. In addition, they found SIRT6 inuences DNA repair mechanism by regulating base excision repair (BER) but not nucleotide excision repair (NER) [6]. Increasing evidence shows SIRT6 regulates BER either by modulating BER factors or regulating the density of chromatin thereby changing the accessibility of DNA damage sites to BER factors, though someone still believes that SIRT6 do not directly inuence BER but inuences the accumulation of DNA damage by regulating metabolism and the level of reactive oxygen species (ROS) base on the fact that deciency of BER do not lead to aging

like phenotype [6, 2325]. Thus, the main controversial that exists between these two points of view is that whether SIRT6 directly involves in the BER mechanism. To solve this issue, we may need to study the details of SIRT6 behavior at the DNA damaging site where BER occurs. Along with BER, DNA double-strand break (DSB) repair is also an important DNA repair mechanism. When DNA encounters severe damage beyond a simple base mismatch, a DSB follows. The occurrence of DSB can cause chromosomal end fusion and disrupts the genome stability via the breakage-fusion-bridge cycle [26]. This begs the question if SIRT6 participates in the DSB repair mechanism? In 2009, McCord et al. demonstrated SIRT6 stabilizes DNA dependent protein kinase on the chromatin and facilitate its joining in DSB repair. SIRT6 forms a macromolecular complex with the DNA DSB repair factorDNA dependent protein kinase, to promote DNA DSB repair. When DSB occurs, SIRT6 dynamically associates with the chromatin and dramatically decrease the H3K9 acetylation level of the cell [27]. Moreover, SIRT6 is essential for the catalytic subunit of DNA dependent protein kinase to translocate to the damaged chromatin and hone in on the induced site-specic DSB chromatin [27]. In 2011, Mao et al. reported cells will recruit SIRT6 to the DNA DSB site under oxidative stress and repair the DSB either by nonhomologous end joining (NHEJ) or homologous recombination. They found oxidative stress promotes the association of SIRT6 and PARP1 and mono-ADP-ribosylates the lysine residue 521 of PARP1, thus activating its poly-ADP-ribosylase activity and enhancing DSB repair under oxidative stress [28]. In summary, the genome instability observed from SIRT6 decient mice and cells indicates the critical roles of SIRT6 in DNA damage repair, and this likely explains the role of SIRT6 in maintaining genome stability. This topic has become one of the hottest areas of modern oncology and cell biology. A well accepted theory concerning tumor origin is that normal cells must accumulate several mutations to undergo malignant transformation. Ample evidence shows mice with deciency of key DNA repair or DNA damage sensing genes are more likely to form cancer [29]. GCIP mutation or downregulation is often observed in multiple human cancers. Interestingly, SIRT6 selectively interacts with GCIP both in vitro and in vivo [30]. Since SIRT6 is critical for maintaining the genome integrity and DNA repair, does SIRT6 function as a tumor suppressor gene and prevent tumor formation? SIRT6 overexpression has been shown to induce apoptosis in cancer cell lines but not in normal cells; however, experiments indicate senescence as well as apoptosis and necrosis is a mechanism that can limit tumor formation. This has cast doubt on its function as a tumor suppressor gene since it can prevent cellular senescence [3133]. How these ndings will explain the

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seemingly contrary function of SIRT6 in its physiological context will be of critical importance in understanding the relationship between SIRT6 and tumorigenesis.

SIRT6 may have distinct effects on metabolism via diverse signaling pathways From SIRT6 knockout mice models, researchers have noted the development of signicant metabolic disorders such as glycopenia, lower level of insulin, complete loss of subcutaneous fat and lordokyphosis [6]. More specically, the phenotype of mice with neural-specic SIRT6 deciency has dramatic implications. The most obvious difference between this tissue specic SIRT6 knockout mice and wild type mice is SIRT6 neural decient mice develop obesity [3437]. This observation has indicated that SIRT6 may function through diverse signaling pathways which may have different or even contradictory downstream effects. Until now, many metabolic pathways have been reported to be regulated by SIRT6. Xiao et al. reported SIRT6 negatively regulates the AKT phosphorylation of serine residue 473 and threonine residue 308 by inhibiting several upstream molecules including insulin receptor, insulin receptor substrate 1 and 2. While when lacking SIRT6, the insulin signaling is enhanced and AKT can be activated, leading to hypoglycemia [35]. Zhong and coworkers [38, 39] discovered SIRT6 inhibits the transcriptional factor Hif1a, which is an important modulator of nutritional stress. SIRT6 decient cells show an elevated level of Hif1a activity and glucose uptake with a decreased level of mitochondrial respiration. The above ndings indicate SIRT6 may be a critical molecular regulator of glucose homeostasis and these discoveries may also serve to provide new therapies to some metabolic disorders such as obesity and diabetes. This reminds us one of the discoveries made by McCay in 1935: retarding rodent growth by limiting calorie intake markedly extends life span [40, 41]. This is the basis of the hypothesis termed calorie restriction (CR): if an individual consumes minimal food so that its energy supply can satisfy his basal consumption, his life span can be prolonged [42, 43]. A central question that has puzzled the scientic world for years is whether Sirtuins are the executioner of CR in mammals. Recently, a group reported that under CR, SIRT3 is benecial to deal with oxidative stress for cells [44]; another group also reported CR promotes cell survival by inducing the expression of SIRT1 [45]. Recently, the relationship between autophagy and aging has also gained great attention. Autophagy is a process of self-eating for cells under stress or starvation [46, 47]. In general, autophagy is believed to retard aging [48]. Since autophagy is a process that mainly happens

under starvation, will this resemble the condition of CR? According to our observation, inhibition of SIRT1&SIRT2 induces apoptosis as well as autophagy in lung cancer cells [49] (unpublished data). How to explain these seemly contradictory results and theories? That has been the focus of our research for the last several years: deciphering how SIRT1&SIRT2 regulates autophagy and whether autophagy is cytoprotective (that is to say autophagy is compensative for apoptosis signaling) or cytotoxic. Will SIRT6 also be a CR executioner? So far, the studies have not panned out in the SIRT6 decient mice. Clearly, more investigations will uncover the relationship between SIRT6 and CR, and the mechanisms by which SIRT6 can regulate life span via CR. Exercise training is a factor that greatly affects metabolism. In general, it is believed aerobic exercise delays emerging of aging phenotypes by oxidizing NADH to NAD? via mitochondrial function [50]. It has also been demonstrated that exercise training relieves the negative effects of aging by stimulating NAD? biosynthesis via SIRT1dependent pathways [51]. Though the molecular relationships between exercise and SIRT6 have not been extensively studied, there is evidence that exercise training can attenuate age-associated increase of SIRT6 [51]. Future studies on what pathways lead to SIRT6 reduction may help us understand how exercise inuences metabolism and delays aging.

SIRT6 may also regulate mammalian aging As discussed above, Sir2 plays a pivotal role in maintaining yeast life span; however, there is still no direct evidence showing its mammalian homolog can regulate mammalian life span. In 2006, Mostoslavsky et al. [6] found that SIRT6 decient mice show an aging phenotype in addition to the genome instability. This discovery has led to the notion that SIRT6 may also be a regulator of mammalian aging. Motif module map analysis suggests constitutive stimulation of the NF-kappa B signaling may accelerate aging in mice [52]. NF-kappa B is an important transcription factor that associates with IjB and locates mainly in the cytoplasm as a heterodimer. When cells suffer from cellular stress or other inducing factors, IjB will be ubiquitinated and degraded. Then, NF-kappa B enters into the nucleus and regulates a subset of downstream genes that control cellular physiological processes toward stress [53]. The most direct evidence of the relationship between SIRT6 and aging came from the discovery by Kawahara et al. They found SIRT6 attenuates NF-kappa B signaling by binding to the RELA subunit of NF-kappa B and deacetylates H3K9 of NF-kappa B targeted gene promoters, thus slowing the aging process [36]. This discovery has built up a connection between SIRT6 and NF-kappa B signaling

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pathway, and elucidated the mechanisms on how SIRT6 inuences life span from the molecular level. Their subsequent experiments demonstrated SIRT6 is common in the promoter region of mice genome, and their occupancy rates on the promoter change dynamically following treatment with TNF-a [54]. Most recently, another group reported SIRT6 affects collagen metabolism and plays a key role in skin anti-aging via NF-kappa B signaling [55]. It is well established that NF-kappa B signaling is a canonical signaling pathway stimulated by inammation and cellular stress. However, recent discovery showed it can also regulate energy homeostasis and affect metabolic adaption by enhancing mitochondrial respiration [2]. When examining this report with the aging phenotype caused by SIRT6 deciency, we can probably draw the conclusion that CR functions through the NF-kappa B pathway. All in all, NF-kappa B signaling is the only pathway reported to be downstream of SIRT6 that can regulate mammalian aging. However, the targets of Sirtuins vary from species to species. Thus, will the already known pathways regulated by NF-kappa B still control aging in other species? Moreover, are there any other pathways that control aging? SIRT1&SIRT2 has been shown to deacetylate FOXO3 under oxidative stress [56, 57]. Stimulation of SIRT1 expression will augment the deacetylation level of FOXO3a, while downregulation of FOXO3a decreases SIRT1 expression. If nutrient withdrawal occurs, p53 recruits FOXO3a to the promoter region of SIRT1 and activates its expression. These three proteins form a loop that serves as a nutrient sensor. Though these proteins separately show their functions in aging, no direct evidence demonstrates their synergistic role in aging [58]. SIRT2 works in a similar way. It increases the expression of FOXO target genes, including manganese superoxide and p27kip1, thus decreasing the ROS level [57]. Will SIRT6 also function through the FOXO family and retard aging by lowering the ROS content of the cell? Motif module map analysis has provided us with powerful tools to study aging related signaling pathways and there are several reasons to believe we can discover the role of SIRT6 and its relationship with mammalian aging.

Fig. 1 Relationships among SIRT6 controlled processes SIRT6 prevents aging through NF-kappa B pathway. However, whether there are several pathways downstream to SIRT6 that regulate aging is still unknown. CR is believed to delay aging and stimulate autophagy in certain tissues [64], while autophagy can also prevent aging through the inactivation of NF-kappa B pathway [65]. Experiments also show NF-kappa B represses autophagy following TNF-a treatment, but in heat shock recovery, NF-kappa B stimulates autophagy and promotes cell survival [66, 67]. Thus, NF-kappa B differentially regulates autophagy. As SIRT1 has been shown to stimulate autophagy, and autophagy expands life span, will SIRT6 prevent aging in the similar manner [68, 69]? SIRT6 has been shown to maintain the genome through NER and DSB repair pathways. By promoting the DNA repair mechanism, SIRT6 can prevent DNA damage-mediated cell cycle arrest induced cellular senescence. As SIRT6 also has an important role in regulating metabolism, SIRT6 may also delay aging by decreasing the ROS produced by metabolic disorders which in another way, protects the DNA from ROS attack

Perspectives With an increasing knowledge about the function of SIRT6, the cell biology community has come to realize the multifaceted functions of SIRT6 are subtly interconnected. For example, metabolic disorders lead to the accumulation of ROS; while the accumulation of ROS can cause DNA damage. If the DNA damage is severe enough, several key molecules such as p53, p16, and p21 will be induced and result in G1 or G2 cell cycle arrest which is usually a prelude of cellular senescence [5962]. To date, what we know about the

relationships among SIRT6 controlled processes can be best summarized as Fig. 1. Will SIRT6 upregulating autophagy via repressing NF-kappa B and then prolong life span? Can NF-kappa B a key regulator of aging? Why overexpression of SIRT6 leads to apoptosis in cancer cells but not normal cells [63]? Elucidating the complex networks regulated by SIRT6 may be the best way, or we could say, an inevitable way to nd out the multiple physiological processes controlled by SIRT6. The most exciting triumphs on SIRT6 research is yet to come!

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