ATM mediated phosphorylation of CHD4 contributes to genome maintenance

Here we describe the chromodomain helicase DNA-binding protein (CHD4) as a target of ATM kinase. We show that ionising radiation (IR)-induced phosphorylation of CHD4 affects its intranuclear organization resulting in increased chromatin binding/retention. We also show assembly of phosphorylated CHD4 foci at sites of DNA damage, which might be required to fulfil its function in the regulation of DNA repair. Consistent with this, cells overexpressing a phospho-mutant version of CHD4 that cannot be phosphorylated by ATM fail to show enhanced chromatin retention after DSBs and display high rates of spontaneous damage.These results provide insight into how CHD4 phosphorylation might be required to remodel chromatin around DNA breaks allowing efficient DNA repair to occur.It is essential that human cells detect, signal and repair DNA damage in order to prevent chromosomal instability or malignant transformation. DNA double strand breaks can be induced by a number of agents including ionising radiation (IR), reactive chemical species and during endogenous DNA processing events such as DNA replication [1]. These breaks must be repaired in order to maintain cellular viability and genomic stability. Once a break has occurred, cells respond by recruiting DNA repair proteins to the DSB sites and initiate a complex DSB response pathway, which includes altered transcriptional and translational regulation, activation of DSB repair and cell cycle checkpoint arrest.It is clear that chromatin restructuring in response to DNA damage is essential for initiation, propagation and termination of DNA repair and may even precede DNA end resection. This process opens the DNA allowing the recruitment of repair factors and the amplification of the checkpoint and downstream signals [2]. Consistent with this, the DNA damage response can be activated in the absence of exogenous DNA damage by the tethering of DNA damage response proteins to chromatin, demonstrating the importance of chromatin as a