Ahel Dragana, Horejsí Zuzana, Wiechens Nicola, Polo Sophie E, Garcia-Wilson Elisa, Ahel Ivan, Flynn Helen, Skehel Mark, West Stephen C, Jackson Stephen P, Owen-Hughes Tom, Boulton Simon J
DNA Damage Response Laboratory, Clare Hall, London Research Institute, South Mimms EN6 3LD, UK.
Science. 2009 Sep 4;325(5945):1240-3. doi: 10.1126/science.1177321. Epub 2009 Aug 6.
Posttranslational modifications play key roles in regulating chromatin plasticity. Although various chromatin-remodeling enzymes have been described that respond to specific histone modifications, little is known about the role of poly[adenosine 5'-diphosphate (ADP)-ribose] in chromatin remodeling. Here, we identify a chromatin-remodeling enzyme, ALC1 (Amplified in Liver Cancer 1, also known as CHD1L), that interacts with poly(ADP-ribose) and catalyzes PARP1-stimulated nucleosome sliding. Our results define ALC1 as a DNA damage-response protein whose role in this process is sustained by its association with known DNA repair factors and its rapid poly(ADP-ribose)-dependent recruitment to DNA damage sites. Furthermore, we show that depletion or overexpression of ALC1 results in sensitivity to DNA-damaging agents. Collectively, these results provide new insights into the mechanisms by which poly(ADP-ribose) regulates DNA repair.
翻译后修饰在调节染色质可塑性中起关键作用。尽管已经描述了各种对特定组蛋白修饰有反应的染色质重塑酶,但关于聚[腺苷5'-二磷酸(ADP)-核糖]在染色质重塑中的作用知之甚少。在这里,我们鉴定出一种染色质重塑酶,ALC1(肝癌中扩增1,也称为CHD1L),它与聚(ADP-核糖)相互作用并催化PARP1刺激的核小体滑动。我们的结果将ALC1定义为一种DNA损伤反应蛋白,其在该过程中的作用通过其与已知DNA修复因子的关联以及其快速的聚(ADP-核糖)依赖性募集到DNA损伤位点而得以维持。此外,我们表明ALC1的缺失或过表达导致对DNA损伤剂的敏感性。总的来说,这些结果为聚(ADP-核糖)调节DNA修复的机制提供了新的见解。