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

Simple item page
dc.citation.firstpage273
dc.citation.journalTitleNature
dc.citation.lastpage277
dc.citation.volumeNumber552
dc.contributor.authorWang, Yugang
dc.contributor.authorGuo, Yusong R.
dc.contributor.authorLiu, Ke
dc.contributor.authorYin, Zheng
dc.contributor.authorLiu, Rui
dc.contributor.authorXia, Yan
dc.contributor.authorTan, Lin
dc.contributor.authorYang, Peiying
dc.contributor.authorLee, Jong-Ho
dc.contributor.authorLi, Xin-jian
dc.contributor.authorHawke, David
dc.contributor.authorZheng, Yanhua
dc.contributor.authorQian, Xu
dc.contributor.authorLyu, Jianxin
dc.contributor.authorHe, Jie
dc.contributor.authorXing, Dongming
dc.contributor.authorTao, Yizhi Jane
dc.contributor.authorLu, Zhimin
dc.date.accessioned2019-12-11T15:44:29Z
dc.date.available2019-12-11T15:44:29Z
dc.date.issued2017
dc.description.abstractHistone 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.
dc.identifier.citationWang, Yugang, Guo, Yusong R., Liu, Ke, et al.. "KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase." <i>Nature,</i> 552, (2017) Springer Nature: 273-277. https://doi.org/10.1038/nature25003.
dc.identifier.digitalnihms946428
dc.identifier.doihttps://doi.org/10.1038/nature25003
dc.identifier.urihttps://hdl.handle.net/1911/107864
dc.language.isoeng
dc.publisherSpringer Nature
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Springer Nature.
dc.titleKAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpost-print
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
nihms946428.pdf
Size:
3.78 MB
Format:
Adobe Portable Document Format
Download
Collections
Faculty Publications
BioSciences Publications