Histone H3 Lysine 14 Acetylation Is Required for Activation of a DNA Damage Checkpoint in Fission Yeast

Yu Wang,Scott P Kallgren,Bharat D Reddy,Karen Kuntz,Luis López-Maury,James Thompson,Stephen Watt,Chun Ma,Haitong Hou,Yang Shi,John R Yates,Jürg Bähler,Matthew J O'Connell,Songtao Jia

doi:10.1074/jbc.m111.329417

Abstract

Histone lysine acetylation has emerged as a key regulator of genome organization. However, with a few exceptions, the contribution of each acetylated lysine to cellular functions is not well understood because of the limited specificity of most histone acetyltransferases and histone deacetylases. Here we show that the Mst2 complex in Schizosaccharomyces pombe is a highly specific H3 lysine 14 (H3K14) acetyltransferase that functions together with Gcn5 to regulate global levels of H3K14 acetylation (H3K14ac). By analyzing the effect of H3K14ac loss through both enzymatic inactivation and histone mutations, we found that H3K14ac is critical for DNA damage checkpoint activation by directly regulating the compaction of chromatin and by recruiting chromatin remodeling protein complex RSC.

Highlights

H3K14 acetylation is required for DNA damage checkpoint activation
We show that the Mst2 complex in Schizosaccharomyces pombe is a highly specific H3 lysine 14 (H3K14) acetyltransferase that functions together with Gcn5 to regulate global levels of H3K14 acetylation (H3K14ac)
By analyzing the effect of H3K14ac loss through both enzymatic inactivation and histone mutations, we found that H3K14ac is critical for DNA damage checkpoint activation by directly regulating the compaction of chromatin and by recruiting chromatin remodeling protein complex RSC

Summary

Conclusion

H3K14 acetylation is required for DNA damage checkpoint activation. Significance: These analyses define the in vivo functions of the acetylation of a single histone lysine residue. By analyzing the effect of H3K14ac loss through both enzymatic inactivation and histone mutations, we found that H3K14ac is critical for DNA damage checkpoint activation by directly regulating the compaction of chromatin and by recruiting chromatin remodeling protein complex RSC. Mutational analyses of the highly specific histone acetyltransferase Rtt109 established the role of H3 lysine 56 acetylation in regulating the DNA damage response [11,12,13,14]. Identification of highly specific histone acetyltransferases and deacetylases is critical for dissecting the functions of individual histone lysine acetylation. Examining the phenotypes of H3K14ac loss by means of both enzymatic inactivation and a H3K14 mutation reveal that H3K14ac plays a major role in regulating DNA damage checkpoint activation

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION