Identification of ‘erasers’ for lysine crotonylated histone marks using a chemical proteomics approach

Bao, Xiucong; Wang, Yi; X, Li; Li, Xiaomeng; Liu, Zheng; Yang, Tangpo; Wong, Chi Fat; Zhang, Jiangwen; Hao, Quan; Li, Xiang

doi:10.7554/elife.02999

Cited by 267 publications

(235 citation statements)

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“…SIRT3 has been reported to interact with chromatin in U2OS cells, resulting in the repression of adjacent genes (68). Interestingly, SIRT3 KD leads to increased lysine crotonylation at five of seven genes analyzed in U2OS cells, along with a significant increase in mRNA levels of three candidate genes (10). These observations suggest that SIRT3 might repress the expression of target genes via modulation of histone lysine crotonylation.…”

Section: Fig 2 Subcellular Localization Of Mammalian Sirtuinsmentioning

confidence: 85%

“…Tan et al described lysine crotonylation as novel histone PTM, which is specifically enriched at active gene promoters and potential enhancers in mammalian genome (155). A very recent study by Bao et al reported that SIRT3 possesses decrotonylase activity, using a similar catalytic mechanism as for acetyl lysine hydrolysis (10,36). siRNA-mediated SIRT3 FIG.…”

Section: Sirt3 Activitymentioning

confidence: 99%

“…However, certain sirtuins are now known to possess alternative catalytic functions-for example, deacylase, decrotonylase, desuccinylase, demalonylase, deglutarylase, and ADP-ribosyltransferase activities (Fig. 1)-that play crucial roles in the regulation of diverse cellular processes (2,10,32,34,36,48,65,72,121,156).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

131

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Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

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Section: Fig 2 Subcellular Localization Of Mammalian Sirtuinsmentioning

confidence: 85%

Section: Sirt3 Activitymentioning

confidence: 99%

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Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

131

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“…Varying acyl moieties and sequence contexts of peptide linkers in the general probe scaffold 1 resulted in a broad set of sirtuin-probes (Figure 1a). [106][107][108] For instance, probe 1 was instrumental for identifying mitochondrial SIRT3 as key regulator of lysine-crotonylation ( Figure 1a). 106 An extension of this concept is the development of sirtuin substrates that also block NAD + binding and thereby prohibit the deacylation reaction.…”

Section: -105mentioning

confidence: 99%

“…[106][107][108] For instance, probe 1 was instrumental for identifying mitochondrial SIRT3 as key regulator of lysine-crotonylation ( Figure 1a). 106 An extension of this concept is the development of sirtuin substrates that also block NAD + binding and thereby prohibit the deacylation reaction. Peptides modified with bulky succinyl-lysines interact with the NAD + binding pocket and thereby inhibit the desuccinylase Sirt5.…”

Section: -105mentioning

confidence: 99%

Probing Chromatin-modifying Enzymes with Chemical Tools

Fischle

Schwarzer

2016

ACS Chem. Biol.

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2 Glossary section/Key words:Epigenetics: Inheritance of gene expression profiles independent of changes in DNA sequence or content.Histones: Small, basic proteins that package eukaryotic DNA into chromatin.Nucleosomes: Nucleosome core particles consist of an octamer of histone proteins (2x H2A, H2B, H3, H4) around which 147 bp of DNA are wrapped. Addition of linker DNA of various length and linker histones (H1) makes up the nucleosome as the basic, repeating unit of chromatin. DNA-Methylation:Enzymatic and none-enzymatic modification of DNA bases with methyl-groups.The methylation of C5 of cytosine is most relevant for gene regulation.Histone modifications: Chemical, posttranslational modifications of specific amino acids of histone proteins. The most abundant modifications are acetylation and methylation of the ε-amino group of lysines, methylation of the guanidino group of arginines and phosphorylation of hydroxyl groups in serines and threonines.Chemical probes: Synthetic molecules designed to interact with a protein of interest in order to study its function and activity.Cosubstrate probes: Chemical probes that are derived from the cellular small molecules that donate modifying groups to DNA and histones such as Adenosine triphosphate (ATP), Acetyl coenzyme A (acetyl-CoA) and S-adenosyl methionine (SAM).Substrate profiling: Proteomic approach to define the pool of target proteins of specific modifying enzymes using cosubstrate probes and mass spectrometry. 3 AbstractChromatin is the universal template of genetic information of all eukaryotic organisms. Chemical modifications of the DNA-packaging histone proteins and the DNA bases are crucial signaling events in directing the use and readout of eukaryotic genomes. The enzymes that install and remove these chromatin modifications as well as the proteins that bind these marks govern information that goes beyond the sequence of DNA. Therefore, these so called epigenetic regulators are intensively studied and represent promising drug targets in modern medicine. We summarize and discuss recent advances in the field of chemical biology that have provided chromatin research with sophisticated tools for investigating the composition, activity and target sites of chromatin modifying enzymes and reader proteins. 4In all eukaryotic cells chromatin, the complex of DNA and histone proteins regulates the functional state of the genome by altering condensation states and active recruitment of regulatory factors. The basic structural unit of chromatin is the nucleosome core particle. It consists of a protein core formed by two copies each of the histone proteins H2A, H2B, H3 and H4 with 147 base pairs of DNA wrapped around.1 Nucleosome core particles are connected by linker DNA, which can bind linker histones thereby giving rise to the fundamental repeating unit of chromatin, the nucleosome. Control of different chromatin states is mediated by a multitude of posttranslational modifications (PTMs) of the histone proteins, including methylation, acetylation and phosphorylatio...

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Crystal structures of SIRT3 reveal that the α2‐α3 loop and α3‐helix affect the interaction with long‐chain acyl lysine

Gai

Jiang

et al. 2016

FEBS Letters

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Edited by Christian Griesinger SIRT1-7 play important roles in many biological processes and age-related diseases. In addition to a NAD + -dependent deacetylase activity, they can catalyze several other reactions, including the hydrolysis of long-chain fatty acyl lysine. To study the binding modes of sirtuins to long-chain acyl lysines, we solved the crystal structures of SIRT3 bound to either a H3K9-myristoylatedor a H3K9-palmitoylated peptide. Interaction of SIRT3 with the palmitoyl group led to unfolding of the a3-helix. The myristoyl and palmitoyl groups bind to the C-pocket and an allosteric site near the a3-helix, respectively. We found that the residues preceding the a3-helix determine the size of the Cpocket. The flexibility of the a2-a3 loop and the plasticity of the a3-helix affect the interaction with long-chain acyl lysine.

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Identification of ‘erasers’ for lysine crotonylated histone marks using a chemical proteomics approach

Cited by 267 publications

References 44 publications

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Probing Chromatin-modifying Enzymes with Chemical Tools

Crystal structures of SIRT3 reveal that the α2‐α3 loop and α3‐helix affect the interaction with long‐chain acyl lysine

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