Lecona Emilio, Rodriguez-Acebes Sara, Specks Julia, Lopez-Contreras Andres J, Ruppen Isabel, Murga Matilde, Muñoz Javier, Mendez Juan, Fernandez-Capetillo Oscar
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
DNA Replication Group, Spanish National Cancer Research Centre, Madrid, Spain.
Nat Struct Mol Biol. 2016 Apr;23(4):270-7. doi: 10.1038/nsmb.3185. Epub 2016 Mar 7.
Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates DNA replication. We have previously shown that chromatin around replisomes is rich in SUMO and poor in Ub, whereas mature chromatin exhibits an opposite pattern. How this SUMO-rich, Ub-poor environment is maintained at sites of DNA replication in mammalian cells remains unexplored. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination. Inhibition or genetic deletion of USP7 leads to the accumulation of Ub on SUMOylated proteins, which are displaced away from replisomes. Our findings provide a model explaining the differential accumulation of SUMO and Ub at replication forks and identify an essential role of USP7 in DNA replication that should be considered in the development of USP7 inhibitors as anticancer agents.
泛素（Ub）和类泛素修饰剂对蛋白质的翻译后修饰调节DNA复制。我们之前已经表明，复制体周围的染色质富含小泛素样修饰物（SUMO）而泛素含量低，而成熟染色质则呈现相反的模式。在哺乳动物细胞中，如何在DNA复制位点维持这种富含SUMO、缺乏泛素的环境仍未得到探索。在这里，我们确定泛素特异性蛋白酶7（USP7）是一种在复制体中富集的SUMO去泛素化酶，它对DNA复制至关重要。通过作用于SUMO和SUMO化蛋白，USP7抵消它们的泛素化。USP7的抑制或基因缺失导致泛素在SUMO化蛋白上积累，这些蛋白从复制体上被取代。我们的研究结果提供了一个模型，解释了SUMO和泛素在复制叉处的差异积累，并确定了USP7在DNA复制中的重要作用，这在开发USP7抑制剂作为抗癌药物时应予以考虑。
