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KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase
Open accessAbstract
Histone modifications, such as the frequently occurring lysine succinylation, are central to the regulation of chromatin-based processes. However, the mechanism and functional consequences of histone succinylation are unknown. Here we show that the α-ketoglutarate dehydrogenase (α-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. We show that succinyl-coenzyme A (succinyl-CoA) binds to KAT2A. The crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA at 2.3 Å resolution shows that succinyl-CoA binds to a deep cleft of KAT2A with the succinyl moiety pointing towards the end of a flexible loop 3, which adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Site-directed mutagenesis indicates that tyrosine 645 in this loop has an important role in the selective binding of succinyl-CoA over acetyl-CoA. KAT2A acts as a succinyltransferase and succinylates histone H3 on lysine 79, with a maximum frequency around the transcription start sites of genes. Preventing the α-KGDH complex from entering the nucleus, or expression of KAT2A(Tyr645Ala), reduces gene expression and inhibits tumour cell proliferation and tumour growth. These findings reveal an important mechanism of histone modification and demonstrate that local generation of succinyl-CoA by the nuclear α-KGDH complex coupled with the succinyltransferase activity of KAT2A is instrumental in histone succinylation, tumour cell proliferation, and tumour development.
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“In the vast majority of these studies to date, histone succinylation is associated with the opening of chromatin and increased gene transcription.”
From Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism (2023) · cites this paper as [42]
Experimental — accuracy not yet measuredIn the citing paper
“Under acidic conditions αKG is protonated and this promotes binding to LDHA and L-2HG production.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [52]
In the citing paper
“The authors demonstrate that this is independent of IDH1 and 2 and primarily mediated by LDHA and malate dehydrogenase (MDH) via “promiscuous” reduction of αKG and this is enhanced by acidic pH52.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [52]
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Metadata
- Authors
- Wang, Y., Guo, Y. R., Liu, K., Yin, Z., Liu, R., Xia, Y., Tan, L., Yang, P., Lee, J.-H., Li, X.-J., Hawke, D., Zheng, Y., Qian, X., Lyu, J., He, J., Xing, D., Tao, Y. J., & Lu, Z.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Rice University (US)
- University of California, Berkeley (US)
- Houston Methodist (US)
- Hangzhou Medical College (CN)
- Wenzhou Medical University (CN)
- Affiliated Hospital of Qingdao University (CN)
- Corresponding author
- Xing, Dongming
- Tao, Yizhi Jane
- Lu, Zhimin
- ORCID
- Venue
- Nature
- Published
- 2017-12
- Volume
- 552
- Issue
- 7684
- Pages
- 273-277
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5841452
- OpenAlex
- W2773645338
- Cited by
- 567
- References
- 20
- Citations by year
- 2026: 84 · 2025: 123 · 2024: 77 · 2023: 61 · 2022: 55 · 2021: 60 · 2020: 47 · 2019: 33 · 2018: 26
- FWCI
- 12.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rice Research Repository (Rice University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Human Genome Research Institute (U54HG007990)
- National Cancer Institute (R01CA109035, R01CA169603, P30CA016672, P50CA127001)
- National Institute of Neurological Disorders and Stroke (R01NS089754)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- GCN5, alpha-ketoglutarate dehydrogenase complex, succinyl-CoA, transcription start sites, gene expression regulation, chromatin modification, tumor cell proliferation
- MeSH terms
- Protein Domains, p300-CBP-Associated Factor, Acetyl Coenzyme A, Acyl Coenzyme A, Animals, Cell Nucleus, Female, Gene Expression Regulation, Histones, Humans, Ketoglutarate Dehydrogenase Complex, Lysine, Models, Molecular, Neoplasms, Protein Binding, Tyrosine, Mutagenesis, Site-Directed, Crystallography, X-Ray, Transcription Initiation Site, Cell Line, Tumor, Cell Proliferation, Mice, Histone Acetyltransferases
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