KAT2A Is a α-KGDH–Dependent Histone Succinyltransferase

Lysine succinylation is a frequently occurring histone modification, but the mechanism and functional effect of histone succinylation are unknown. The histone acetyltransferase KAT2A binds to acetyl-CoA to transfer its acetyl group to histones, and Wang, Guo, and colleagues found that KAT2A also binds to oxoglutarate dehydrogenase (OGDH), a component of the α-ketoglutarate dehydrogenase (α-KGDH) complex that catalyzes the conversion of α-ketoglutarate (α-KG) to succinyl-CoA, raising the possibility that KAT2A may have analogous roles in histone acetylation and histone succinylation. Consistent with this hypothesis, depletion of KAT2A reduced histone H3 succinylation and acetylation. KAT2A co-localized with α-KGDH and histone H3 in the nucleus, and an in vitro succinylation assay indicated that KAT2A directly succinylated histone H3. Determination of the crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA to 2.3 Å revealed a structure similar to the KAT2A–acetyl-CoA complex with a flexible loop 3 that adopts different conformation in succinyl-CoA–bound and acetyl-CoA–bound forms. Succinyl-CoA had a higher affinity for KAT2A than acetyl-CoA, and nuclear α-KGDH generated succinyl-CoA, providing a source for KAT2A-mediated histone succinylation. Mutation of tyrosine 645 in the KAT2A loop 3 reduced H3 succinylation, without altering H3 acetylation. KAT2A directly succinylated histone H3 on lysine 79, most commonly near the transcription start site of genes, demonstrating that KAT2A can function as a histone succinyltransferase, although in different complexes KAT2A functions as a histone acetyltransferase instead. H3K79 succinylation was a stable modification and occurred at 7,186 genes, altering gene expression. These gene expression changes promoted cell proliferation and tumor growth, and the growth of intracranially injected glioblastoma cells was suppressed by blocking the α-KGDH complex from entering the nucleus or expressing mutant KAT2A^Y645A, indicating that H3K79 succinylation promotes tumor growth. In addition to identifying KAT2A coupled with the α-KGDH complex as a histone H3 succinyl transferase, these findings suggest that histone succinylation induces widespread gene expression changes that promote tumor growth.

Wang Y, Guo YR, Liu K, Yin Z, Liu R, Xia Y, et al. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature 2017;552:273–7.

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