Genome integrity is continuously threatened by DNA damage arising from both exogenous and endogenous sources. In response to DNA damage cells activate a signal transduction cascade, known as the DNA damage checkpoint, that results in the activation of DNA repair pathways. Timely termination of this signalling cascade is then essential for the resumption of normal cell growth once DNA damage has been repaired.
A new study from Professor Tony Kouzarides’ group in collaboration with Professor Steve Jackson’s group, both at the Gurdon Institute, shows how this transition between DNA damage checkpoint activation and termination is regulated in baker’s yeast. The authors identified a DNA-damage-regulated histone modification in Saccharomyces cerevisiae, phosphorylation of histone H4 threonine 80, and showed that it triggers DNA damage checkpoint termination by promoting the timely recruitment of Rtt107 protein to displace the checkpoint adaptor Rad9, thereby interrupting the checkpoint-signalling cascade.
It is well known that the DNA damage checkpoint acts as a barrier during early tumourigenesis, and that its inactivation enhances tumour progression. Therefore, understanding the mechanisms by which cells inactivate the checkpoint-signalling cascade may reveal new potential therapeutic targets for cancer treatment.
