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15.11.18 Phosphorylation of histone H4T80 triggers DNA-damage-checkpoint recovery

last modified Nov 19, 2018 10:32 AM
The Kouzarides and Jackson labs tease out the series of biochemical events, including a histone modification, that allows cells to recover from the DNA damage checkpoint
15.11.18 Phosphorylation of histone H4T80 triggers DNA-damage-checkpoint recovery

Graphical abstract from the paper

Phosphorylation of Histone H4T80 Triggers DNA Damage Checkpoint Recovery

Millan-Zambrano G et al. (2018) Mol. Cell Vol 72, Issue 4, Pages 625-635.e4

 

 

 

Highlights from the paper

  • Histone H4T80 phosphorylation regulates DNA damage checkpoint recovery
  • In response to DNA damage, PAK family kinase Cla4 phosphorylates H4T80
  • H4T80 phosphorylation promotes timely recruitment of the scaffold protein Rtt107
  • H4T80ph-bound Rtt107 counteracts Rad9 binding to H3K79me

 

Summary from the paper

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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Read more about research in the Kouzarides lab and watch Tony Kouzarides describe his research on video.

 

Find out more about research in the Jackson lab and watch Steve Jackson describe his research.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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