Overexpression of Eaf1, a subunit of the NuA4 lysine acetyltransferase complex, rescues growth defects in the budding yeast H3K36M oncohistone model via histone H4 tail acetylation

Histone proteins are critical for regulating nucleic acid transactions, including gene expression. Specific missense mutations in histone genes have been linked to oncogenesis, creating oncohistones. One of the first identified oncohistones converts K36 in histone H3 to M (H3K36M). While humans have 15 H3 genes, the Saccharomyces cerevisiae genome contains only two H3 genes. As H3 shares 90% sequence identity between budding yeast and humans, the budding yeast system provides an ideal model for study of H3K36M. We previously identified the catalytic subunit of the NuA4 lysine acetyltransferase complex as a high copy suppressor of growth defects in H3K36 mutant yeast cells. Here, we demonstrate that the NuA4 scaffold Eaf1 suppresses mutant H3K36 growth defects. We show that this suppression by Eaf1 is dependent on the Eaf1 HSA domain. To examine whether the role of NuA4 in acetylating histone H4 is required for suppression of H3K36 growth defects, we altered the four NuA4 target lysines within H4 (K5, 8, 12, and 16) to create quadruple histone mutants with all four of these lysines converted to alanine (H4-4K→A) or arginine (H4-4K→R). These H4 mutants have reduced viability and disrupted global H4 acetylation. Eaf1 cannot suppress growth defects in these H4 acetylation mutants, suggesting Eaf1-mediated suppression is dependent on acetylation of H4 N-terminal tails. We further show that inhibiting NuA4 activity in H3K36M human cells limits their oncogenic potential. Together, this work defines a mechanistic connection between H3K36 and H4 N-terminal tail acetylation in the context of a cancer-causing mutation.