Males-absent-on-the-first (MOF, also called MYST1 or KAT8) is a histone acetyltransferase (HAT) belonging to the MOZ, Ybf2/Sas3, Sas2 and Tip60 (MYST) family. MOF has been shown to possess a specific HAT activity towards Lys16 of histone H4 (H4K16) 1. Homozygous knockout of MOF in mice results in loss of H4K16 acetylation and embryonic lethality, indicating that MOF and H4K16 acetylation are essential for embryogenesis and genome stability in mammals 2. Downregulation of human MOF (hMOF) leads to dramatic nuclear morphological deformation and inhibition of cell cycle progression 3, and has recently been correlated with primary breast carcinoma and medulloblastoma 4.

To investigate whether Lys274 is autoacetylated, the wild-type and mutant hMOF proteins were incubated with acetyl-CoA and subsequently subjected to western blot with an antibody specific to acetylated lysine. Intriguingly, for all the hMOF proteins except the K274Q mutant, the acetylation levels prior to the acetyl-CoA incubation and the extents of the increase after the incubation correlated well with their respective HAT activities (Supplementary information, Figure S2), indicating that the acetylation of hMOF is catalyzed by hMOF itself. Although the K274Q mutant had an HAT activity comparable to that of the G327E mutant, its acetylation was undetected, which is in agreement with our MS data that Lys274 is the main acetylation site of the hMOF catalytic domain.

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