Phosphorylation of histone H4T80 triggers DNA damage checkpoint recovery

Gonzalo Millan-Zambrano, Helena Santos-Rosa, Fabio Puddu, Samuel C. Robson, Stephen P. Jackson, Tony Kouzarides

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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.
Original languageEnglish
Pages (from-to)625-635.e4
JournalMolecular Cell
Issue number4
Early online date25 Oct 2018
Publication statusPublished - 15 Nov 2018


  • Cla4
  • DNA damage checkpoint
  • H4T80ph
  • histone modifications
  • PAK
  • Rad53
  • Rad9
  • Rtt107


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