Abstract
SummaryIn response to genotoxic stress, cells activate a signaling cascade known as the DNA damage checkpoint (DDC) that leads to a temporary cell cycle arrest and activation of DNA repair mechanisms. Because persistent DDC activation compromises cell viability, this process must be tightly regulated. However, despite its importance, the mechanisms regulating DDC recovery are not completely understood. Here, we identify a DNA-damage-regulated histone modification in Saccharomyces cerevisiae, phosphorylation of H4 threonine 80 (H4T80ph), and show that it triggers checkpoint inactivation. H4T80ph is critical for cell survival to DNA damage, and its absence causes impaired DDC recovery and persistent cell cycle arrest. We show that, in response to genotoxic stress, p21-activated kinase Cla4 phosphorylates H4T80 to recruit Rtt107 to sites of DNA damage. Rtt107 displaces the checkpoint adaptor Rad9, thereby interrupting the checkpoint-signaling cascade. Collectively, our results indicate that H4T80ph regulates DDC recovery.
Highlights
Genome integrity is continuously threatened by DNA damage arising from both exogenous and endogenous sources
Defective accumulation of H4T80ph in cla4D mutant cells is not due to impaired double-strand break (DSB) induction (Figure S3D). These results indicate that Cla4 is responsible for H4T80 phosphorylation at sites of DNA damage
H4T80ph Regulates the DNA Damage Checkpoint To examine functions of H4T80ph, we investigated the origin of the DNA damage hypersensitivity of the H4T80A mutant strain
Summary
Genome integrity is continuously threatened by DNA damage arising from both exogenous and endogenous sources. The eukaryotic genome is compacted into chromatin, whose fundamental repeating unit is the nucleosome. Nucleosomes consist of 147 base pairs of DNA tightly wrapped around a core histone octamer, which is composed of two copies of histones H2A, H2B, H3, and H4 (Luger et al, 1997). Chromatin structure regulates all DNA-based processes, including the DDR. In this regard, histones are subject to post-translational modifications that change chromatin structure and provide docking sites for other proteins. Histones are subject to post-translational modifications that change chromatin structure and provide docking sites for other proteins These modifications are dynamically deposited and removed by chromatin-modifying enzymes in a tightly regulated manner (Bannister and Kouzarides, 2011)
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