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

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.

SIRT5 inhibits peroxisomalACOX1 to prevent oxidative damage and is downregulated in liver cancer

“…For a long time, the mammalian cellular transferase for lysine succinylation has not been well characterized, while succinylation was regarded as a nonenzymatic modification. Recently, Wang et al showed that histone acetyltransferase KAT2A coupled with α‐ketoglutarate dehydrogenase complex (α‐KGDH) can succinylate nuclear histone H3. However, the succinyl‐transferase in non‐nuclear compartments still remains unknown.…”

Advances of Proteomics in Novel PTM Discovery: Applications in Cancer Therapy

“…The results show that the pentose phosphate pathway and the endoplasmic reticulum protein processing pathway might be regulated via lysine succinylation of their core enzymes, suggesting a novel tumorigenesis mechanism for breast cancer therapy . Lysine acetyltransferase 2A (KAT2A/GCN5) has been identified as a succinyltransferase that succinylates histone H3 at lysine 79, regulating a series of gene transcriptions and influencing tumor cell proliferation and growth . In gastric cancer, S100A10, which is highly expressed in cancer tissues, was found to be stabilized at lysine residue 47.…”

Histone Lysine and Genomic Targets of Histone Acetyltransferases in Mammals

“…Cell-free assay, shRNA in cells GCN5 succinylates H3K79 in cell-free assays and shRNA KD of GCN5 or a GCN5 HAT dead mutant reduce H3K79succ in U87 cells, and H3K79succ, H3K9ac and H3K14ac in U251 cells [106] TIP60 H2A-K5, H3K14 H4K5, H4K8 H4K12, H4K16…”