HP1-β mobilization promotes chromatin changes that initiate the DNA damage response

Publisher Website
Google Scholar
Abstract
The earliest known response to chromosomal DNA breakage is the phosphorylation of the histone H2AX. Ayoub et al. have now identified a dynamic change in chromatin that promotes this phosphorylation step. DNA breaks swiftly mobilize the chromatin factor HP1-β, and via a previously unrecognized signalling cascade involving a phosphorylation step carried out by casein kinase 2, H2AX becomes phosphorylated and the DNA damage response is under way. A phosphorylation step carried out by casein kinase 2, coupled with mobilization of the chromatin factor HP1-β, helps to initiate the DNA damage response by promoting phosphorylation of histone H2AX. 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 (γ)-H2AX—which recruits molecules that sense or signal the presence of DNA breaks, activating the response that leads to repair2,3—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)-β (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-β on amino acid Thr 51 accompanies mobilization, releasing HP1-β 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 repair4,5,6, suppresses Thr 51 phosphorylation and HP1-β mobilization in living cells. CK2 inhibition, or a constitutively chromatin-bound HP1-β 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.