Peptide Switch Is Essential for Sirt1 Deacetylase Activity

Kang, Hyeog; Suh, Jeong‐Yong; Jung, Young-Sang; Jung, Jaewon; Kim, Myung K.; Chung, Jay H.

doi:10.1016/j.molcel.2011.07.038

Cited by 91 publications

(94 citation statements)

References 57 publications

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“…Given its role in human health, SIRT1 activities in vivo are tightly regulated (Nemoto et al 2004;Chen et al 2005;Wang et al 2006;Abdelmohsen et al 2007;Kim et al 2007;Yang et al 2007;Sasaki et al 2008). Recently, we and others have demonstrated that SIRT1's activity is modulated by protein-protein interaction through the DBC1 (Deleted in Breast Cancer 1) protein (Kim et al 2008;Zhao et al 2008;Kang et al 2011). Using DBC1 knockout mice, we have also shown that DBC1 is a major regulator of SIRT1 in vivo (Escande et al 2010).…”

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confidence: 77%

Regulation of SIRT1 activity by genotoxic stress

Yuan¹,

Luo²,

Liu

et al. 2012

Genes Dev.

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SIRT1 regulates a variety of cellular functions, including cellular stress responses and energy metabolism. SIRT1 activity is negatively regulated by DBC1 (Deleted in Breast Cancer 1) through direct binding. However, how the DBC1-SIRT1 interaction is regulated remains unclear. We found that the DBC1-SIRT1 interaction increases following DNA damage and oxidative stress. The stress-induced DBC1-SIRT1 interaction requires the ATMdependent phosphorylation of DBC1 at Thr 454, which creates a second binding site for SIRT1. Finally, we showed that the stress-induced DBC1-SIRT1 interaction is important for cell fate determination following genotoxic stress. These results revealed a novel mechanism of SIRT1 regulation during genotoxic stress.Supplemental material is available for this article.Received January 28, 2012; revised version accepted March 8, 2012. SIRT1, a mammalian homolog for yeast silent information regulator 2 (SIR2), is a NAD + -dependent deacetylase that belongs to the class III histone deacetylases (Imai et al. 2000). SIRT1 and its orthologs were initially implicated in the regulation of life span in lower organisms, including yeast, Caenorhabditis elegans, and Drosophila melanogaster (Lin et al. 2000;Tissenbaum and Guarente 2001;Wood et al. 2004), although recent studies suggested that some of the reported effects may be due to confounding effects of genetic assays (Burnett et al. 2011). In mammals, SIRT1 participates in various cellular functions ranging from differentiation and development to metabolism and cell survival by deacetylating various proteins, including histones, transcription factors, and cell cycle and apoptosis regulatory proteins (Bordone and Guarente 2005;Schwer and Verdin 2008;Finkel et al. 2009;Haigis and Sinclair 2010;Yu and Auwerx 2010). Given its role in human health, SIRT1 activities in vivo are tightly regulated (Nemoto et al. 2004;Chen et al. 2005;Wang et al. 2006;Abdelmohsen et al. 2007;Kim et al. 2007;Yang et al. 2007;Sasaki et al. 2008). Recently, we and others have demonstrated that SIRT1's activity is modulated by protein-protein interaction through the DBC1 (Deleted in Breast Cancer 1) protein (Kim et al. 2008;Zhao et al. 2008;Kang et al. 2011). Using DBC1 knockout mice, we have also shown that DBC1 is a major regulator of SIRT1 in vivo (Escande et al. 2010). However, how the DBC1-SIRT1 interaction is regulated remains unclear. In this study, we found that, following DNA damage and oxidative stress, DBC1 binds more tightly to SIRT1. We further characterized the mechanism underlying this stress-induced DBC1-SIRT1 interaction and its functional significance. Results and Discussion DBC1-SIRT1 interaction increased following cellular stressPrevious studies have shown that p53 acetylation, which is deacetylated by SIRT1, increases following DNA damage (Luo et al. 2001;Vaziri et al. 2001). In addition to p53 acetylation, the acetylation of other SIRT1 target proteins also increases, suggesting that SIRT1 activity is inhibited by DNA damage (Fig. 1A). When we examined the prot...

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confidence: 77%

Regulation of SIRT1 activity by genotoxic stress

Yuan¹,

Luo²,

Liu

et al. 2012

Genes Dev.

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“…Of interest is that Kang et al (70) recently found that the amino acids 631-655 in SIRT1 (what they call the essential for SIRT1 activity region) are necessary for SIRT1 activation. Moreover, these authors proposed that this region is important for the regulation of SIRT1 by DBC1.…”

Section: Discussionmentioning

confidence: 99%

Role of Deleted in Breast Cancer 1 (DBC1) Protein in SIRT1 Deacetylase Activation Induced by Protein Kinase A and AMP-activated Protein Kinase

Nin

Escande

Chini

et al. 2012

Journal of Biological Chemistry

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Background: DBC1 is a key regulator of SIRT1 activity, although it is unknown how the SIRT1-DBC1 interaction is regulated. Results: PKA and AMPK activate SIRT1 by disrupting the interaction between SIRT1 and DBC1. Conclusion: We provide mechanistic evidence on how the SIRT1-DBC1 complex is regulated. Significance: The SIRT1-DBC1 complex constitutes a target for the development of drugs to activate SIRT1.

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“…Another 25-amino acid peptide called essential for SIRT1 activity (ESA) is also required for catalysis. 20 The spectrum of acetylated protein substrates of SIRT1 is vast; at least 79 have been described (Table 1) including a large number of important nuclear proteins (such as p53, Rb, NF-κB, and CBP/p300) along with a variety of cytoplasmic proteins. The identification of cytoplasmic substrates for a protein that appears to be primarily nuclear in interphase cells is one of the many apparent paradoxes in the field.…”

Section: Monographsmentioning

confidence: 99%

SIRT1 is a Highly Networked Protein That Mediates the Adaptation to Chronic Physiological Stress

et al. 2013

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SIRT1 is a NAD + -dependent protein deacetylase that has a very large number of established protein substrates and an equally impressive list of biological functions thought to be regulated by its activity. Perhaps as notable is the remarkable number of points of conflict concerning the role of SIRT1 in biological processes. For example, evidence exists suggesting that SIRT1 is a tumor suppressor, is an oncogene, or has no effect on oncogenesis. Similarly, SIRT1 is variably reported to induce, inhibit, or have no effect on autophagy. We believe that the resolution of many conflicting results is possible by considering recent reports indicating that SIRT1 is an important hub interacting with a complex network of proteins that collectively regulate a wide variety of biological processes including cancer and autophagy. A number of the interacting proteins are themselves hubs that, like SIRT1, utilize intrinsically disordered regions for their promiscuous interactions. Many studies investigating SIRT1 function have been carried out on cell lines carrying undetermined numbers of alterations to the proteins comprising the SIRT1 network or on inbred mouse strains carrying fixed mutations affecting some of these proteins. Thus, the effects of modulating SIRT1 amount and/or activity are importantly determined by the genetic background of the cell (or the inbred strain of mice), and the effects attributed to SIRT1 are synthetic with the background of mutations and epigenetic differences between cells and organisms. Work on mice carrying alterations to the Sirt1 gene suggests that the network in which SIRT1 functions plays an important role in mediating physiological adaptation to various sources of chronic stress such as calorie restriction and calorie overload. Whether the catalytic activity of SIRT1 and the nuclear concentration of the co-factor, NAD + , are responsible for modulating this activity remains to be determined. However, the effect of modulating SIRT1 activity must be interpreted in the context of the cell or tissue under investigation. Indeed, for SIRT1, we argue that context is everything.

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Peptide Switch Is Essential for Sirt1 Deacetylase Activity

Cited by 91 publications

References 57 publications

Regulation of SIRT1 activity by genotoxic stress

Regulation of SIRT1 activity by genotoxic stress

Role of Deleted in Breast Cancer 1 (DBC1) Protein in SIRT1 Deacetylase Activation Induced by Protein Kinase A and AMP-activated Protein Kinase

SIRT1 is a Highly Networked Protein That Mediates the Adaptation to Chronic Physiological Stress

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