Structural Basis of Sirtuin 6-Catalyzed Nucleosome Deacetylation

Wang, Zhipeng A.; Markert, Jonathan; Whedon, Samuel D.; Abeywardana, Maheeshi Yapa; Lee, Kwang-Woon; Jiang, Hanjie; Suarez, Carolay; Lin, Hening; Farnung, Lucas; Cole, Philip A.

doi:10.1021/jacs.2c13512

Cited by 28 publications

(31 citation statements)

References 61 publications

(120 reference statements)

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“…It is important to note that several recent studies demonstrate that SIRT6 has intrinsic affinity to nucleosomes (undamaged DNA). 28,31,32 Our results, however, suggest that SIRT6 can also be activated by DNA lesions. It is known that SIRT6 can be quickly (within 5 s) recruited to DNA damage sites in response to oxidative stress.…”

Section: ■ Methods and Materialscontrasting

confidence: 56%

“…Several structural biology studies suggest that the C-terminal extension of SIRT6 is highly unstructured, 28,31,41 as predicted by AlphaFold (Figure S6). 42,43 One intriguing model is that the binding of SIRT6 to DNA lesion is primarily regulated by the N-and C-terminal extensions.…”

Section: ■ Methods and Materialsmentioning

confidence: 80%

“…This result suggests that TSA and DNA may compete, at least partially, for the same binding site. These initial findings, together with several recent reports showing that SIRT6 demonstrates a nucleosome-dependent deacetylase activity, ,− prompted us to investigate whether the deacetylation activity of SIRT6 can be stimulated by DNA as part of its normal function. Indeed, when DNA [ssDNA, dsDNA (calf thymus DNA sheared to an average size less than 2000bp), or cut plasmid] was included in the reaction, SIRT6 deacetylation was significantly improved toward the peptide substrate (Figure A and Table ).…”

Section: Resultsmentioning

confidence: 99%

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Activation of SIRT6 Deacetylation by DNA Strand Breaks

Kang,

Hamza,

Curry

et al. 2023

ACS Omega

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SIRT6 is an emerging regulator of longevity. Overexpression of SIRT6 extends the lifespan of mice. Conversely, SIRT6 knockout mice demonstrate severe metabolic defects and a shortened lifespan. The discrepancy between SIRT6's weak in vitro activity and robust in vivo activity has led to the hypothesis that this enzyme can be activated in response to DNA damage in cells.Here, we demonstrate that the deacetylase activity of SIRT6 can be stimulated by DNA strand breaks for synthetic peptide and histone substrates. The mechanism of activation is further explored by using an integrative chemical biology approach. SIRT6 can be preferentially activated by DNA lesions harboring a 5′-phosphate. The N-and C-termini of SIRT6 are strictly required for DNA break-induced activation. Additionally, the defatty-acylase activity of SIRT6 is also sensitive to DNA breaks, although the physiological significance needs further investigation. Collectively, our study sheds important light on the cellular regulation of diverse SIRT6 activities and suggests possible strategies for effective SIRT6 activation.

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Section: ■ Methods and Materialscontrasting

confidence: 56%

Section: ■ Methods and Materialsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

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Activation of SIRT6 Deacetylation by DNA Strand Breaks

Kang,

Hamza,

Curry

et al. 2023

ACS Omega

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“… [18b,21] Overall, the model confidence is high or very high for the N‐terminal domain and the Rossman fold containing the catalytic domain. For the N‐terminal domain this likely reflects that an X‐ray crystal structure is available (residues 5–73; PDB 5IQZ) [19] and for the Rossman fold domain there is high sequence similarity to SIRT6, for which several structures are available (e.g., PDB 3 K35, [22] 6XV1, [23] 7CL0, [24] 8F86, [16b] 8G57 [16c] )…”

Section: Resultsmentioning

confidence: 99%

Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide‐Activated Sirtuin 7**

Bolding,

Nielsen,

Jensen

et al. 2023

Angew Chem Int Ed

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The sirtuins are NAD+‐dependent lysine deacylases, comprising seven isoforms (SIRT1–7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ε‐N‐acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms; in part, due to a lack of chemical tools to specifically probe SIRT7 activity. Here we expressed SIRT7 and, using small‐angle X‐ray scattering, reveal SIRT7 to be a monomeric enzyme with low degree of globular flexibility in solution. We developed a fluorogenic assay for investigation of the substrate preferences of SIRT7 and to evaluate compounds that modulate its activity. We report several mechanism‐based SIRT7 inhibitors as well as de novo cyclic peptide inhibitors selected from mRNA‐display library screening that exhibit selectivity for SIRT7 over other sirtuin isoforms, stabilize SIRT7 in cells, and cause increase in the acetylation H3K18.

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“…The Sirtuin protein family consists of seven members (SIRT1–SIRT7), serving as NAD + -dependent lysine deacetylases and located at different subcellular locations . Sirtuins play a crucial role in many physiological processes such as regulating lifespan extension and controlling various metabolic pathways. , As an important member of Sirtuins, SIRT6 extensively participates in the deacetylation of histones (e.g., H3 , ) and non-histones, which are closely associated with DNA damage repair, maintenance of telomere integrity, transcriptional regulation, and cellular energy metabolism. − …”

Section: Introductionmentioning

confidence: 99%

Deciphering the Allosteric Activation Mechanism of SIRT6 Using Molecular Dynamics Simulations

Zhao,

Du,

et al. 2023

J. Chem. Inf. Model.

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As a member of the histone deacetylase protein family, the NAD + -dependent SIRT6 plays an important role in maintaining genomic stability and regulating cell metabolism. Interestingly, SIRT6 has been found to have a preference for hydrolyzing long-chain fatty acyls relative to deacetylation, and it can be activated by fatty acids. However, the mechanisms by which SIRT6 recognizes different substrates and can be activated by small molecular activators are still not well understood. In this study, we carried out extensive molecular dynamic simulations to shed light on these mechanisms. Our results revealed that the binding of the myristoylated substrate stabilizes the catalytically favorable conformation of NAD + , while the binding of the acetyl-lysine substrate leads to a loose binding of NAD + in SIRT6. Based on these observations, we proposed a reasonable allosteric binding mode for myristic acid, which can enhance the catalytic activity of SIRT6 by stabilizing the binding of NAD + with His131 as well as the acetylated substrate. Furthermore, our molecular dynamics simulations demonstrated that synthetic SIRT6 activators, such as UBCS039, MDL-801, and 12q, block the flipping of ribose in NAD + and therefore can stabilize substrate−NAD + −His131 interactions in a manner similar to fatty acids. In summary, our newly proposed activation mechanism of SIRT6 highlights the importance of protein−substrate interactions, which would facilitate the rational design of new SIRT6 activators.

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Structural Basis of Sirtuin 6-Catalyzed Nucleosome Deacetylation

Cited by 28 publications

References 61 publications

Activation of SIRT6 Deacetylation by DNA Strand Breaks

Activation of SIRT6 Deacetylation by DNA Strand Breaks

Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide‐Activated Sirtuin 7**

Deciphering the Allosteric Activation Mechanism of SIRT6 Using Molecular Dynamics Simulations

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