Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Cell. 2010 Jun 11;141(6):970-81. doi: 10.1016/j.cell.2010.04.038.
DNA double-strand breaks (DSBs) initiate extensive local and global alterations in chromatin structure, many of which depend on the ATM kinase. Histone H2A ubiquitylation (uH2A) on chromatin surrounding DSBs is one example, thought to be important for recruitment of repair proteins. uH2A is also implicated in transcriptional repression; an intriguing yet untested hypothesis is that this function is conserved in the context of DSBs. Using a novel reporter that allows for visualization of repair protein recruitment and local transcription in single cells, we describe an ATM-dependent transcriptional silencing program in cis to DSBs. ATM prevents RNA polymerase II elongation-dependent chromatin decondensation at regions distal to DSBs. Silencing is partially dependent on E3 ubiquitin ligases RNF8 and RNF168, whereas reversal of silencing relies on the uH2A deubiquitylating enzyme USP16. These findings give insight into the role of posttranslational modifications in mediating crosstalk between diverse processes occurring on chromatin.
DNA 双链断裂 (DSB) 会引发染色质结构的广泛局部和全局改变，其中许多改变依赖于 ATM 激酶。染色质上 DSB 周围的组蛋白 H2A 泛素化 (uH2A) 就是一个例子，它被认为对修复蛋白的募集很重要。uH2A 也与转录抑制有关；一个有趣但未经测试的假设是，这种功能在 DSB 情况下是保守的。我们使用一种新的报告基因，允许在单细胞中可视化修复蛋白的募集和局部转录，描述了一种在 DSB 顺式的 ATM 依赖性转录沉默程序。ATM 防止 RNA 聚合酶 II 延伸依赖性染色质解凝聚在 DSB 远端的区域。沉默部分依赖于 E3 泛素连接酶 RNF8 和 RNF168，而沉默的逆转则依赖于 uH2A 去泛素化酶 USP16。这些发现深入了解了翻译后修饰在介导染色质上发生的不同过程之间的串扰中的作用。
