Regulation of genome stability by a novel histone acetyltransferase

Coupling DNA synthesis to nucleosome assembly Cartoon depicting components of H3 lysine 56 acetylation and its role in coupling DNA synthesis with nucleosome assembly. Rtt109 is a novel histone acetyltransferase that forms a complex with Vps75 and catalyzes this acetylation. The histone chaperone Asf1 is proposed to present H3/H4 complexes to the Rtt109/Vps75 complex to regulate H3-K56 acetylation, which leads to deposition of the histones onto DNA to form nucleosomes and thus to promote genome stability.

Chromatin, the organized structure of DNA and structural proteins including histones, regulates a variety of cellular processes. For instance, the newly-synthesized DNA strands must be immediately reassembled into the original chromatin state during replication, and uncoupling of DNA synthesis to subsequent chromatin assembly leads to genome instability, one of the hallmarks of cancer cells. Thus, it is critical to understand how DNA synthesis is coupled to chromatin assembly. Recent studies from our lab and others have discovered that acetylation of lysine 56 on H3 (H3-K56) may play a role in regulation of chromatin assembly during S phase of the cell cycle. Acetylation of H3-K56 occurs transiently during S phase. Cells with altered acetylation of H3-K56 are highly sensitive to DNA damaging agents, suggesting that this modification is important for maintaining genome stability.

Using a genome-wide approach, we have identified two proteins in the yeast S. cerevisiae, Rtt109 and Asf1, that regulate H3-K56 acetylation. Asf1 is a histone H3 and H4 chaperone functioning in chromatin assembly, whereas Rtt109 is a previously uncharacterized protein that forms a complex with Vps75. Biochemical analysis on Rtt109 allows us to demonstrate that Rtt109 is a unique histone acetyltransferase as it shares no sequence homology to any other known HATs discovered so far. Moreover, we have shown Rtt109 is required to maintain genome stability. These studies lay a solid foundation for our future studies on the regulation of H3-K56 acetylation during S phase of the cell cycle catalyzed by Rtt109 and modulated by Vps75 and Asf1, on the mechanisms by which this modification regulates genome stability, and on whether this modification is mis-regulated in cancer cells.