Phosphorylation of Histone H4T80 Triggers DNA Damage Checkpoint Recovery.

Millan-Zambrano, Gonzalo 
Santos-Rosa, Helena 
Robson, Samuel C 
Jackson, Stephen P 

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In 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.

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Cla4, DNA damage checkpoint, H4T80ph, PAK, Rad53, Rad9, Rtt107, histone modifications, Cell Cycle Checkpoints, Cell Cycle Proteins, Checkpoint Kinase 2, DNA Damage, DNA Repair, Histones, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Serine-Threonine Kinases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction
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Mol Cell
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Elsevier BV
Cancer Research UK (17001)
Cancer Research UK (18796)
Wellcome Trust (206388/Z/17/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
The Kouzarides laboratory is supported by Cancer Research UK (grant reference RG17001). The Jackson laboratory is supported by Cancer Research UK (grant reference C6/A18796) and Wellcome Trust (Investigator Award 206388/Z/17/Z). Both laboratories benefit from core support from the Wellcome Trust (Core Grant reference WT203144) and Cancer Research UK (grant reference C6946/A24843). G.M.-Z. was funded by an EMBO long-term fellowship (ALTF907- 2014).