Histone acetylation dynamics in repair of DNA double-strand breaks.

Packaging of eukaryotic genome into chromatin is a major obstacle to cells encountering DNA damage caused by external or internal agents. For maintaining genomic integrity, the double-strand breaks (DSB) must be efficiently repaired, as these are the most deleterious type of DNA damage. The DNA breaks have to be detected in chromatin context, the DNA damage response (DDR) pathways have to be activated to repair breaks either by non- homologous end joining and homologous recombination repair.

DDK/Hsk1 phosphorylates and targets fission yeast histone deacetylase Hst4 for degradation to stabilize stalled DNA replication forks.

In eukaryotes, paused replication forks are prone to collapse, which leads to genomic instability, a hallmark of cancer. Dbf4-dependent kinase (DDK)/Hsk1 is a conserved replication initiator kinase with conflicting roles in replication stress response. Here, we show that fission yeast DDK/Hsk1 phosphorylates sirtuin, Hst4 upon replication stress at C-terminal serine residues.

Fission Yeast Sirtuin Hst4 Functions in Preserving Genomic Integrity by Regulating Replisome Component Mcl1.

The Schizosaccharomyces pombe sirtuin Hst4, functions in the maintenance of genome stability by regulating histone H3 lysine56 acetylation (H3K56ac) and promoting cell survival during replicative stress. However, its molecular function in DNA damage survival is unclear. Here, we show that hst4 deficiency in the fission yeast causes S phase delay and DNA synthesis defects.