生物谷報道：對染色體DNA斷裂的已知最早的反應(yīng)是組蛋白H2AX的磷酸化。現(xiàn)在,，Ayoub等人識別出能夠促進(jìn)這一磷酸化步驟的染色質(zhì)中的一個動態(tài)變化。DNA的斷裂迅速使染色質(zhì)因子HP1beta動員起來,，而且通過一個涉及由酪蛋白激酶-2完成的磷酸化步驟的一個以前沒有被識別出來的信號級聯(lián)，H2AX被磷酸化,，DNA損傷修復(fù)反應(yīng)得以進(jìn)行,。
生物谷推薦英文原文：
Nature 453, 682-686 (29 May 2008) | doi:10.1038/nature06875; Received 14 November 2007; Accepted 28 February 2008; Published online 27 April 2008
HP1- mobilization promotes chromatin changes that initiate the DNA damage response
Nabieh Ayoub1, Anand D. Jeyasekharan1, Juan A. Bernal1 & Ashok R. Venkitaraman1
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: [email protected]).
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 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)- (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 repair4, 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.
