Lysine succinylation and lysine malonylation in histones
Open accessAbstract
Histone protein post-translational modifications (PTMs) are significant for gene expression and DNA repair. Here we report the identification and validation of a new type of PTM in histones, lysine succinylation. The identified lysine succinylated histone peptides were verified by MS/MS of synthetic peptides, HPLC co-elution, and isotopic labeling. We identified 13, 7, 10, and 7 histone lysine succinylation sites in HeLa, mouse embryonic fibroblast, Drosophila S2, and Saccharomyces cerevisiae cells, respectively. We demonstrated that this histone PTM is present in all eukaryotic cells we examined. Mutagenesis of succinylation sites followed by functional assays implied that histone lysine succinylation can cause unique functional consequences. We also identified one and two histone lysine malonylation sites in HeLa and S. cerevisiae cells, respectively. Our results therefore increase potential combinatorial diversity of histone PTMs and suggest possible new connections between histone biology and metabolism.
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Thirty-five nonredundant histone lysine succinylation sites were found, six of which overlapped with an earlier mouse-cell report.
“Given the reported mitochondrial localization of SIRT5, it is somewhat surprising that we identified 35 nonredundant histone Lys succinylation sites, six of those sites overlapping with our first report of histone succinylation sites in mouse cells (Xie et al., 2012).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Xie et al., 2012
Large variety of novel histone marks, such as formylation, propionylation, butyrylation, malonylation, and succinylation, have been identified by tandem mass spectrometry.
“In fact, a large variety of novel histone marks, such as formylation, propionylation, butyrylation, malonylation and succinylation have recently been identified by tandem mass spectrometry (Chen et al., 2007; Wisniewski et al., 2008; Xie et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Xie et al., 2012
In DI-treated BMDMs, genes involved in Phase II conjugation, glutathione conjugation and biological oxidations are upregulated.
“Lampropoulou and colleagues (2016) reported an upregulation of genes involved in Phase II conjugation, glutathione conjugation and biological oxidations from an RNA-seq screen performed in DI-treated BMDMs50.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [50]
Itaconate modulates inflammation by competitively inhibiting SDH and succinate oxidation.
“Lampropoulou and colleagues (2016) suggested that mechanistically the ability of itaconate to modulate inflammation arose from its ability to competitively inhibit SDH and succinate oxidation50.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [50]
BMDMs activated by LPS and pre-treated with dimethyl itaconate exhibit potent inhibition of pro-inflammatory mediators including NO, ROS and cytokines IL-6, IL-12p70 and IL-1β.
“Importantly, Lampropoulou and colleagues (2016) first demonstrated that bone-marrow derived macrophages (BMDMs) activated by LPS and pre-treated with a cell permeable methyl ester derivative of itaconate, dimethyl itaconate (DI), exhibited potent inhibition of pro-inflammatory mediators including nitic oxide (NO), ROS and the cytokines IL-6, IL-12p70 and IL-1β13,50.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [50]
Irg1-deficient BMDMs exhibit a significant increase in production of IL-12, IL-6, NO, and under NLRP3 inflammasome-activating conditions, increased IL-1β and IL-18.
“Furthermore, Irg1-deficient BMDMs, whereby genetic deletion of Irg1 completely abolished itaconate synthesis, exhibited a significant increase in the production of IL-12, IL-6, NO, and under conditions that activate the NLRP3 inflammasome, increased IL-1β and IL-1850.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [50]
Itaconate is an important immunomodulatory metabolite that negatively regulates the inflammatory response and cytokine production.
“Since 2016, several key studies have uncovered a role for itaconate as a crucial anti-inflammatory metabolite that negatively regulates the inflammatory response and cytokine production50,59–61, as shown in Figure 3.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [50]
Cites
Chromatin modifications and their function
Kouzarides, T. (2007) · Cell · doi:10.1016/j.cell.2007.02.005 · Cited by 10,883 · see citing works
Jenuwein, T., & Allis, C. D. (2001) · Science · doi:10.1126/science.1063127 · Cited by 9,756 · see citing works
Heintzman, N. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., Barrera, L. O., Van Calcar, S., Qu, C., Ching, K. A., et al. (2007) · Nature Genetics · doi:10.1038/ng1966 · Cited by 3,398 · see citing works
The diverse functions of histone lysine methylation
Martin, C., & Zhang, Y. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1761 · Cited by 2,066 · see citing works
Substrate and Functional Diversity of Lysine Acetylation Revealed by a Proteomics Survey
Kim, S. C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L., et al. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.06.026 · Cited by 1,487 · see citing works
Self-citationA PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling
Wysocka, J., Swigut, T., Xiao, H., Milne, T. A., Kwon, S. Y., Landry, J., Kauer, M., Tackett, A. J., Chait, B. T., Badenhorst, P. W., et al. (2006) · Nature · doi:10.1038/nature04815 · Cited by 1,186 · see citing works
Extraction, purification and analysis of histones
Shechter, D., Dormann, H. L., Allis, C. D., & Hake, S. B. (2007) · Nature Protocols · doi:10.1038/nprot.2007.202 · Cited by 1,054 · see citing works
Identification of lysine succinylation as a new post-translational modification
Zhang, Z., Tan, M., Xie, Z., Dai, L., Chen, Y., & Zhao, Y. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.495 · Cited by 1,027 · see citing works
Self-citationMultivalent engagement of chromatin modifications by linked binding modules
Ruthenburg, A. J., Li, H., Patel, D. J., & Allis, C. D. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2298 · Cited by 1,015 · see citing works
Dot1p Modulates Silencing in Yeast by Methylation of the Nucleosome Core
van Leeuwen, F., Gafken, P. R., & Gottschling, D. E. (2002) · Cell · doi:10.1016/s0092-8674(02)00759-6 · Cited by 853 · see citing works
Wysocka, J., Swigut, T., Milne, T. A., Dou, Y., Zhang, X., Burlingame, A. L., Roeder, R. G., Brivanlou, A. H., & Allis, C. D. (2005) · Cell · doi:10.1016/j.cell.2005.03.036 · Cited by 820 · see citing works
Bromodomain: an acetyl‐lysine binding domain
Zeng, L., & Zhou, M. (2002) · FEBS Letters · doi:10.1016/s0014-5793(01)03309-9 · Cited by 751 · see citing works
The first identification of lysine malonylation substrates and its regulatory enzyme
Peng, C., Lu, Z., Xie, Z., Cheng, Z., Chen, Y., Tan, M., Luo, H., Zhang, Y., He, W., Yang, K., et al. (2011) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.012658 · Cited by 751 · see citing works
Self-citationp53 post-translational modification: deregulated in tumorigenesis
Dai, C., & Gu, W. J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.09.002 · Cited by 523 · see citing works
Acetylation in Histone H3 Globular Domain Regulates Gene Expression in Yeast
Xu, F., Zhang, K., & Grunstein, M. R. (2005) · Cell · doi:10.1016/j.cell.2005.03.011 · Cited by 394 · see citing works
Chemical derivatization of histones for facilitated analysis by mass spectrometry
Garcia, B. A., Mollah, S., Ueberheide, B. M., Busby, S. A., Muratore‐Schroeder, T. L., Shabanowitz, J., & Hunt, D. F. (2007) · Nature Protocols · doi:10.1038/nprot.2007.106 · Cited by 389 · see citing works
β- N -acetylglucosamine (O-GlcNAc) is part of the histone code
Sakabe, K., Wang, Z., & Hart, G. W. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009023107 · Cited by 372 · see citing works
DNA binding within the nucleosome core
Luger, K., & Richmond, T. J. (1998) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(98)80007-9 · Cited by 303 · see citing works
MacDonald, M. J., Fahien, L. A., Brown, L. J., Hasan, N. M., Buss, J. D., & Kendrick, M. A. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00218.2004 · Cited by 244 · see citing works
Mechanisms of epigenetic inheritance
Martin, C. C., & Zhang, Y. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.04.002 · Cited by 236 · see citing works
Probing Nucleosome Function: A Highly Versatile Library of Synthetic Histone H3 and H4 Mutants
Dai, J., Hyland, E. M., Yuan, D., Huang, H., Bader, J. S., & Boeke, J. D. (2008) · Cell · doi:10.1016/j.cell.2008.07.019 · Cited by 229 · see citing works
Self-citationNakanishi, S., Sanderson, B. W., Delventhal, K. M., Bradford, W. D., Staehling‐Hampton, K., & Shilatifard, A. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1454 · Cited by 201 · see citing works
SnapShot: p53 Posttranslational Modifications
Kruse, J.-P., & Gu, W. J. (2008) · Cell · doi:10.1016/j.cell.2008.05.020 · Cited by 170 · see citing works
Characterization of histones and their post-translational modifications by mass spectrometry
Garcia, B. A., Shabanowitz, J., & Hunt, D. F. (2006) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2006.11.022 · Cited by 143 · see citing works
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The metabolic signature of macrophage responses
Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T., & Castegna, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01462 · Cited by 2,021 · see citing works
SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways
Park, J., Chen, Y., Tishkoff, D. X., Peng, C., Tan, M., Dai, L., Xie, Z., Zhang, Y., Zwaans, B. M. M., Skinner, M. E., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.06.001 · Cited by 1,000 · see citing works
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Tan, M., Peng, C., Anderson, K. A., Chhoy, P., Xie, Z., Dai, L., Park, J., Chen, Y., Huang, H., Zhang, Y., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.014 · Cited by 844 · see citing works
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Sabari, B. R., Tang, Z., Huang, H., Yong-Gonzalez, V., Molina, H., Kong, H. E., Dai, L., Shimada, M., Cross, J. R., Zhao, Y., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.02.029 · Cited by 659 · see citing works
Self-citationNishida, Y., Rardin, M. J., Carrico, C., He, W., Sahu, A. K., Gut, P., Najjar, R., Fitch, M., Hellerstein, M., Gibson, B. W., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.022 · Cited by 481 · see citing works
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Self-citationCoupling Krebs cycle metabolites to signalling in immunity and cancer
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Wang, F., Wang, K., Xu, W., Zhao, S., Ye, D., Wang, Y., Xu, Y., Zhou, L., Chu, Y., Zhang, C., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.05.065 · Cited by 340 · see citing works
Wei, W., Liu, X., Chen, J., Gao, S., Lu, L., Zhang, H., Ding, G., Wang, Z., Chen, Z., Shi, T., et al. (2017) · Cell Research · doi:10.1038/cr.2017.68 · Cited by 304 · see citing works
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Kelly, R. D. W., Chandru, A., Watson, P. J., Song, Y., Blades, M., Robertson, N. S., Jamieson, A. G., Schwabe, J. W. R., & Cowley, S. M. (2018) · Scientific Reports · doi:10.1038/s41598-018-32927-9 · Cited by 138 · see citing works
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He, D., Wang, Q., Li, M., Damaris, R. N., Yi, X., Cheng, Z., & Yang, P. (2016) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b00805 · Cited by 124 · see citing works
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Maze, I., Shen, L., Zhang, B., Garcia, B. A., Shao, N., Mitchell, A., Sun, H., Akbarian, S., Allis, C. D., & Nestler, E. J. (2014) · Nature Neuroscience · doi:10.1038/nn.3816 · Cited by 100 · see citing works
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Zhou, M., Malhan, N., Ahkami, A. H., Engbrecht, K., Myers, G., Dahlberg, J., Hollingsworth, J., Sievert, J. A., Hutmacher, R., Madera, M., et al. (2020) · Methods · doi:10.1016/j.ymeth.2019.10.007 · Cited by 23 · see citing works
- Authors
- Xie, Z., Dai, J., Dai, L., Tan, M., Cheng, Z., Wu, Y., Boeke, J. D., & Zhao, Y.
- Affiliations
- University of Chicago (US)
- Johns Hopkins University (US)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Zhao, Yingming
- ORCID
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 11
- Issue
- 5
- Pages
- 100-107
- ISSN
- 1535-9476 (ISSN-L)
- PMC
- PMC3418837
- OpenAlex
- W2148741118
- Cited by
- 613
- References
- 24
- Citations by year
- 2026: 33 · 2025: 40 · 2024: 41 · 2023: 39 · 2022: 54 · 2021: 61 · 2020: 53 · 2019: 44 · 2018: 56 · 2017: 51 · 2016: 43 · 2015: 46 · 2014: 25 · 2013: 23 · 2012: 3
- FWCI
- 12.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular & Cellular Proteomics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA126832)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082664)
- National Center for Research Resources (U54RR020389, L40 RR020389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- histone modifications, histone function, eukaryotic cells, Saccharomyces cerevisiae, Drosophila S2 cells, HeLa cells, mouse embryonic fibroblasts
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, Drosophila, Histones, Humans, Lysine, Malonates, Molecular Sequence Data, Peptide Fragments, Phenotype, Protein Processing, Post-Translational, Saccharomyces cerevisiae, Succinates, Conserved Sequence, Protein Structure, Tertiary, Amino Acid Substitution, Saccharomyces cerevisiae Proteins, Mice, Tandem Mass Spectrometry
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