HP1-β mobilization promotes chromatin changes that initiate the DNA damage response
HP1-β mobilization promotes chromatin changes that initiate the DNA damage response
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DOI：
10.1038/nature06875
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发表时间：
2008-05-29
期刊：
影响因子：
64.8
通讯作者：
Venkitaraman, Ashok R.
中科院分区：
文献类型：
--
作者：
Ayoub, Nabieh;Jeyasekharan, Anand D.;Venkitaraman, Ashok R.
在DNA损伤后几分钟，变体组蛋白H2 AX被磷酸肌醇激酶家族的蛋白激酶磷酸化，包括ATM、ATR或DNA-PK 1。磷酸化（γ）-H2 AX-招募分子，感知或发出DNA断裂的信号，激活导致修复的反应（2，3）-是已知最早的染色体DNA断裂标记。在这里，我们发现了染色质的动态变化，这种变化促进了哺乳动物细胞中H2 AX的磷酸化。DNA断裂迅速动员异染色质蛋白1（HP 1）-β（也称为CBX 1），这是一种与组蛋白H3结合的染色质因子，组蛋白H3在赖氨酸9上甲基化（H3 K9 me）。组蛋白尾部修饰的局部变化不明显.相反，氨基酸Thr 51上的HP 1-β磷酸化伴随着动员，通过破坏将其染色体结构域折叠在H3 K9 me周围的氢键从染色质释放HP 1-β。酪蛋白激酶2（CK 2）是一种参与DNA损伤传感和修复的酶（4-6），抑制酪蛋白激酶2（CK 2）可抑制活细胞中Thr 51磷酸化和HP 1-β动员。CK 2抑制或组成性染色质结合的HP 1-β突变体减少H2 AX磷酸化。我们的发现揭示了一种未被识别的信号级联反应，它有助于启动DNA损伤反应，通过修饰组蛋白编码介体蛋白HP 1而不是编码本身来改变染色质。
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 (gamma)-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)-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(4-6), 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.