HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response.
Minutes after DNA damage, the variant histone H2AX is phosphorylated by protein kinases of the phosphoinositide kinase family, including ATM, ATR or DNA-PK. Phosphorylated (gamma)-H2AX-which recruits molecules that sense or signal the presence of DNA breaks, activating the response that leads to repair-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)-beta (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-beta on amino acid Thr 51 accompanies mobilization, releasing HP1-beta 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, suppresses Thr 51 phosphorylation and HP1-beta mobilization in living cells. CK2 inhibition, or a constitutively chromatin-bound HP1-beta 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.
Ayoub
Nabieh
N
The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
Jeyasekharan
Anand D
AD
Bernal
Juan A
JA
Venkitaraman
Ashok R
AR
D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005347:Fibroblasts; D006657:Histones / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008745:Methylation; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction
C000715593:CBX1 protein, human; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D000090266:Chromobox Protein Homolog 5; D047390:Casein Kinase II