ATM mediated phosphorylation of CHD4 contributes to genome maintenance

Signal Transduction Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia. .
Genome Integrity 01/2011; 2(1):1. DOI: 10.1186/2041-9414-2-1
Source: PubMed


In order to maintain cellular viability and genetic integrity cells must respond quickly following the induction of cytotoxic double strand DNA breaks (DSB). This response requires a number of processes including stabilisation of the DSB, signalling of the break and repair. It is becoming increasingly apparent that one key step in this process is chromatin remodelling.
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.

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    • "Our findings show that prolonged binding of RNF8 promotes large-scale changes in chromatin structure, which prompted us to test whether RNF8 recruits a chromatin remodelling enzyme to the array, which, in turn, modulates chromatin structure. To address this possibility, we tethered mCherry- LacR-RNF8 to the array in NIH2/4 cells and subsequently analysed the localization of a collection of fluorescent protein-tagged chromatin remodelling enzymes that have previously been linked to DNA repair: BRG1 (Park et al, 2006; Lee et al, 2010), ACF1 (Ura et al, 2001; Luijsterburg et al, 2009; Lan et al, 2010), ALC1 (Ahel et al, 2009; Gottschalk et al, 2009) and CHD4, which is the ATPase subunit of the NuRD (Nucleosome Remodelling and histone Deacetylation) complex (Xue et al, 1998), that has recently been implicated in the DDR (Pegoraro et al, 2009; Larsen et al, 2010; Polo et al, 2010; Smeenk et al, 2010; Urquhart et al, 2011). While BRG1, ACF1 and ALC1 did not co-localize with tethered RNF8 (Supplementary Figure S4), recruitment of the SNF2-like chromatin remodeller CHD4 was observed upon immobilization of mCherry-LacR-RNF8 (Figure 3A and G). "
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