Letter

KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase

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Abstract

Histone modifications, such as the frequently occurring lysine succinylation1,2, 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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Gene Expression Omnibus

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Acknowledgements

We thank L. Li at the University of Texas Health Science at Houston for technical support and D. Norwood and T. Locke for critical reading of this manuscript. This work was supported by National Institute of Neurological Disorders and Stroke grant R01 NS089754 (Z.L.), National Cancer Institute grants 2R01 CA109035 (Z.L.), R01 CA169603 (Z.L.), MD Anderson Support Grant P30CA016672, Welch Foundation grant C-1565 (Y.J.T.), and the National Institutes of Health Brain Cancer Specialized Program of Research Excellence (2P50 CA127001). Z.L. is a Ruby E. Rutherford Distinguished Professor.

Author information

Author notes

    • Yugang Wang
    •  & Yusong R. Guo

    These authors contributed equally to this work.

    • Dongming Xing
    • , Yizhi Jane Tao
    •  & Zhimin Lu

    These authors jointly supervised this work.

Affiliations

  1. Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Yugang Wang
    • , Rui Liu
    • , Yan Xia
    • , Jong-Ho Lee
    • , Xin-jian Li
    • , Yanhua Zheng
    •  & Zhimin Lu
  2. Department of BioSciences, Rice University, Houston, Texas 77005, USA

    • Yusong R. Guo
    •  & Yizhi Jane Tao
  3. Department of Statistics, University of California, Berkeley, California 94720, USA

    • Ke Liu
  4. Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, Texas 77030, USA

    • Zheng Yin
  5. Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA

    • Lin Tan
    •  & Peiying Yang
  6. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • David Hawke
  7. People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China

    • Xu Qian
    •  & Jianxin Lyu
  8. Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China

    • Jianxin Lyu
  9. Laboratory of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China

    • Jie He
  10. Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266061, China

    • Dongming Xing
  11. Qingdao Cancer Institute, Qingdao, Shandong 266061, China

    • Dongming Xing
  12. School of Life Sciences, Tsinghua University, Beijing, 100084, China

    • Dongming Xing
  13. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Zhimin Lu
  14. MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas 77030, USA

    • Zhimin Lu

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Contributions

Z.L., Y.J.T., D.X., and Y.W. conceived and designed the study and wrote the manuscript. Y.W., R.L., Y.X., Y.Z., and J.L. performed the biochemistry experiments to identify the succinyltransferase activity of KAT2A. Y.R.G., Y.W., and Y.J.T. generated co-crystal structures of KAT2A and Co-enzyme A analogues. Z.Y. and K.L. performed bioinformatics analyses. L.T. and P.Y. performed quantification analyses of acetyl-CoA and succinyl-CoA in cells. X.L. identified the nuclear localization sequence on DLST. X.Q. performed animal tissue studies. D.H. identified KAT2A-mediated histone H3 succinylation residue. P.Y., J.-H.L., D.X., J.L., and J.H. provided technical support.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Dongming Xing or Yizhi Jane Tao or Zhimin Lu.

Reviewer Information Nature thanks J. Denu, C. Frezza and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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