A new regulatory pathway responding to hyper-acetylation of histone H3K56

Acetylation of histone H3 on lysine 56 is a modification that marks newly synthesized histones and sites of DNA damage. Deacetylating this residue is equally as important as its acetylation. In the model organism Saccharomyces cerevisiae two redundant proteins of the sirtuin family, Hst3 and Hst4, keep the acetylation levels low outside the S-phase of the cell cycle. In the absence of those deacetylases (in cells that are Δhst3 Δhst4) there is hyper acetylation of H3K56 throughout the entire cell cycle and on both new and old histones, conferring genomic instability that leads to phenotypes of defective growth and thermosensitivity.

Here we report that cells experiencing hyper acetylation of H3K56 share a lethal interaction with the lack of the protein kinase Dun1, in a manner that is independent of DUN1’s known role in upregulation of dNTP levels in the cells. We also report that Dun1 is a negative regulator of the alternative clamp loader Ctf18, but not of the other alternative clamp loaders, Elg1 and Rad24.

We find that two point mutations known to abolish the connection between Ctf18 and DNA polymerase ε, working at the leading strand, is enough to restore viability to cells lacking DU1. Together, our findings argue that in the presence of hyper acetylation of H3K56, Dun1p plays a critical role in maintaining viability against harmful effects caused by the actions of Ctf18p at the fork.