1. The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK

Correspondence to: Ashok R. Venkitaraman¹ Correspondence and requests for materials should be addressed to A.R.V. (Email: arv22@cam.ac.uk).

Abstract

Minutes after DNA damage, the variant histone H2AX is phosphorylated by protein kinases of the phosphoinositide kinase family, including ATM, ATR or DNA-PK¹. Phosphorylated ()-H2AX—which recruits molecules that sense or signal the presence of DNA breaks, activating the response that leads to repair^{2, 3}—is the earliest known marker of chromosomal DNA breakage. Here we identify a dynamic change in chromatin that promotes H2AX phosphorylation in mammalian cells. DNA breaks swiftly mobilize heterochromatin protein 1 (HP1)- (also called CBX1), a chromatin factor bound to histone H3 methylated on lysine 9 (H3K9me). Local changes in histone-tail modifications are not apparent. Instead, phosphorylation of HP1- on amino acid Thr 51 accompanies mobilization, releasing HP1- from chromatin by disrupting hydrogen bonds that fold its chromodomain around H3K9me. Inhibition of casein kinase 2 (CK2), an enzyme implicated in DNA damage sensing and repair^{4, 5, 6}, suppresses Thr 51 phosphorylation and HP1- mobilization in living cells. CK2 inhibition, or a constitutively chromatin-bound HP1- mutant, diminishes H2AX phosphorylation. Our findings reveal an unrecognized signalling cascade that helps to initiate the DNA damage response, altering chromatin by modifying a histone-code mediator protein, HP1, but not the code itself.

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