posted on 2022-01-19, 21:13authored byYi-Hsun Ho, Rong Huang
Acetylation at the α-N-terminus
(Nα) is the most abundant
modification detected on histone H4 and H2A, which is catalyzed by
N-terminal acetyltransferase D (NatD or NAA40). Histone H4 and H2A
contain an identical N-terminal SGRGK sequence that is enriched with
post-translational modifications (PTMs) and frequently occurred oncogenic
mutations known as “oncohistone” mutations. However,
there is a lack of information on how oncohistone mutations and other
PTMs affect NatD-catalyzed acetylation. Herein, we determined how
the local chemical environment on the N-terminal SGRGK sequence impacts
NatD-catalyzed Nα-acetylation on histone H4/H2A. Our studies
indicate that all oncohistone mutations at SGRG suppressed NatD-catalyzed
acetylation. Meanwhile, H4 Ser1 phosphorylation and Arg3 methylation
negatively impact the NatD-mediated acetylation, but the Lys5 acetylation
only has a marginal effect. This work reveals the impacts of oncohistone
mutations on NatD activity and unravels the crosstalk between NatD
and PTMs, implying potential regulatory mechanism of NatD and highlighting
different avenues to interrogate the NatD-mediated pathway in the
future.