Nature：DNA损伤修复的机制
生物谷报道：对染色体DNA断裂的已知最早的反应是组蛋白H2AX的磷酸化。现在，Ayoub等人识别出能够促进这一磷酸化步骤的染色质中的一个动态变化。DNA的断裂迅速使染色质因子HP1beta动员起来，而且通过一个涉及由酪蛋白激酶-2完成的磷酸化步骤的一个以前没有被识别出来的信号级联，H2AX被磷酸化，DNA损伤修复反应得以进行。
生物谷推荐英文原文：
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: arv22@cam.ac.uk).
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.
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