Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks.
Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks.
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DOI：
10.1083/jcb.200510130
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发表时间：
2006-04-24
期刊：
影响因子：
--
通讯作者：
Lukas J
中科院分区：
文献类型：
--
作者：
Bekker-Jensen S;Lukas C;Kitagawa R;Melander F;Kastan MB;Bartek J;Lukas J
我们发现，DNA双链断裂（DSB）诱导复杂的亚区室化的基因组监视监管机构。由γ-H2 AX标记的染色质被共济失调毛细血管扩张突变（ATM）激酶、Mdc 1和53 BP 1占据。相反，修复因子（Rad 51、Rad 52、BRCA 2和FANCD 2）、ATM和Rad-3相关（ATR）级联（ATR、ATR相互作用蛋白和复制蛋白A）以及DNA钳（Rad 17和Rad 9）在由单链DNA（ssDNA）描绘的亚染色质微区室中积累。BRCA 1和Mre 11-Rad 50-Nbs 1复合物与这两个隔室相互作用。重要的是，一些核心DSB调节子不形成细胞学上可辨别的病灶。这些进一步细分为连接DSB与细胞核其余部分的蛋白质（Chk 1和-2），在未加工的DSB处组装（DNA-PK/Ku 70），以及作为预组装复合物存在于染色质上但在DNA损伤后局部修饰（Smc 1/Smc 3）。最后，检查点效应物如p53和Cdc 25 A根本不在DSB中积累。我们建议，DSB监管机构根据其居住地点的子分类提供了一个有用的框架，了解他们参与不同的基因组监测过程。
We show that DNA double-strand breaks (DSBs) induce complex subcompartmentalization of genome surveillance regulators. Chromatin marked by γ-H2AX is occupied by ataxia telangiectasia–mutated (ATM) kinase, Mdc1, and 53BP1. In contrast, repair factors (Rad51, Rad52, BRCA2, and FANCD2), ATM and Rad-3–related (ATR) cascade (ATR, ATR interacting protein, and replication protein A), and the DNA clamp (Rad17 and -9) accumulate in subchromatin microcompartments delineated by single-stranded DNA (ssDNA). BRCA1 and the Mre11–Rad50–Nbs1 complex interact with both of these compartments. Importantly, some core DSB regulators do not form cytologically discernible foci. These are further subclassified to proteins that connect DSBs with the rest of the nucleus (Chk1 and -2), that assemble at unprocessed DSBs (DNA-PK/Ku70), and that exist on chromatin as preassembled complexes but become locally modified after DNA damage (Smc1/Smc3). Finally, checkpoint effectors such as p53 and Cdc25A do not accumulate at DSBs at all. We propose that subclassification of DSB regulators according to their residence sites provides a useful framework for understanding their involvement in diverse processes of genome surveillance.
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