Abstract
In Saccharomyces cerevisiae, acetylation of lysine 56 (Lys-56) in the globular domain of histone H3 plays an important role in response to genotoxic agents that interfere with DNA replication. However, the regulation and biological function of this modification are poorly defined in other eukaryotes. Here we show that Lys-56 acetylation in Schizosaccharomyces pombe occurs transiently during passage through S-phase and is normally removed in G(2). Genotoxic agents that cause DNA double strand breaks during replication elicit a delay in deacetylation of histone H3 Lys-56. In addition, mutant cells that cannot acetylate Lys-56 are acutely sensitive to genotoxic agents that block DNA replication. Moreover, we show that Spbc342.06cp, a previously uncharacterized open reading frame, encodes the functional homolog of S. cerevisiae Rtt109, and that this protein acetylates H3 Lys-56 both in vitro and in vivo. Altogether, our results indicate that both the regulation of histone H3 Lys-56 acetylation by its histone acetyltransferase and histone deacetylase and its role in the DNA damage response are conserved among two distantly related yeast model organisms.
Highlights
Ated by histone acetyltransferases (HATs)7 and is reversible as the acetyl group can be removed through the action of histone deacetylases (HDACs)
In S. cerevisiae this modification plays a key role in surviving DNA damage as cells in which histone H3 cannot be acetylated at lysine 56 (Lys-56) are acutely sensitive to genotoxic agents that interfere with DNA replication (10 –13)
We demonstrate that histone H3 Lys-56 acetylation in S. pombe occurs transiently during S-phase, but is maintained in response to genotoxic agents that interfere with DNA replication
Summary
Chromosome loss, and a high incidence of spontaneous DNA damage [16, 17]. Until recently, the HAT responsible for H3 Lys-56 acetylation was unknown leaving a gap in fully understanding the regulation of this mark. To determine whether histone H3 Lys-56 acetylation is conserved in other eukaryotes, we investigated the presence and the regulation of this modification in Schizosaccharomyces pombe, which is estimated to have diverged from S. cerevisiae between 320 and 420 million years ago, making fission and budding yeast as distantly related to each other as mammals are to either yeast [23] In this manuscript, we demonstrate that histone H3 Lys-56 acetylation in S. pombe occurs transiently during S-phase, but is maintained in response to genotoxic agents that interfere with DNA replication. We provide evidence that H3 Lys-56-Ac is catalyzed by a fission yeast orthologue of S. cerevisiae Rtt109 and that the absence of Rtt109 or the H3 K56R mutation confers sensitivity to genotoxic agents Both the cell cycle and DNA damage regulation of histone H3 Lys-56 acetylation are conserved in S. pombe
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