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

Nature. 2017 Dec 14;552(7684):273-277. doi: 10.1038/nature25003.

Yugang Wang ¹, Yusong R Guo ², Ke Liu ³, Zheng Yin ⁴, Rui Liu ¹, Yan Xia ¹, Lin Tan ⁵, Peiying Yang ⁵, Jong-Ho Lee ¹, Xin-Jian Li ¹, David Hawke ⁶, Yanhua Zheng ¹, Xu Qian ⁷, Jianxin Lyu ⁷ ⁸, Jie He ⁹, Dongming Xing ¹⁰ ¹¹ ¹², Yizhi Jane Tao ², Zhimin Lu ¹ ¹³ ¹⁴

Affiliations

1 Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
2 Department of BioSciences, Rice University, Houston, Texas 77005, USA.
3 Department of Statistics, University of California, Berkeley, California 94720, USA.
4 Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, Texas 77030, USA.
5 Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
6 Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
7 People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
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.
9 Laboratory of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.
10 Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266061, China.
11 Qingdao Cancer Institute, Qingdao, Shandong 266061, China.
12 School of Life Sciences, Tsinghua University, Beijing, 100084, China.
13 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
14 MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas 77030, USA.

PMID: 29211711 DOI: 10.1038/nature25003

Abstract

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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