Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Nat Cell Biol. 2013 May;15(5):526-32. doi: 10.1038/ncb2729. Epub 2013 Apr 28.
Cdc48 (also known as p97), a conserved chaperone-like ATPase, plays a strategic role in the ubiquitin system. Empowered by ATP-driven conformational changes, Cdc48 acts as a segregase by dislodging ubiquitylated proteins from their environment. Ufd1, a known co-factor of Cdc48, also binds SUMO (ref. 6), but whether SUMOylated proteins are subject to the segregase activity of Cdc48 as well and what these substrates are remains unknown. Here we show that Cdc48 with its co-factor Ufd1 is SUMO-targeted to proteins involved in DNA double-strand break repair. Cdc48 associates with SUMOylated Rad52, a factor that assembles the Rad51 recombinase on chromatin. By acting on the Rad52-Rad51 complex, Cdc48 curbs their physical interaction and displaces the proteins from DNA. Genetically interfering with SUMO-targeting or segregase activity leads to an increase in spontaneous recombination rates, accompanied by aberrant in vivo Rad51 foci formation in yeast and mammalian cells. Our data thus suggest that SUMO-targeted Cdc48 restricts the recombinase Rad51 by counterbalancing the activity of Rad52. We propose that Cdc48, through its ability to associate with co-factors that have affinities for ubiquitin and SUMO, connects the two modification pathways for protein degradation or other regulatory purposes.
CDC48（也称为 p97）是一种保守的伴侣样 ATP 酶，在泛素系统中发挥着重要作用。CDC48 通过 ATP 驱动的构象变化获得动力，作为一种分拣酶，将泛素化的蛋白质从其环境中解离出来。Ufd1 是 CDC48 的已知共因子，也与 SUMO（参考文献 6）结合，但 SUMO 化蛋白是否也受到 CDC48 分拣酶的作用，以及这些底物是什么，目前尚不清楚。在这里，我们表明，CDC48 与其共因子 Ufd1 被 SUMO 靶向到参与 DNA 双链断裂修复的蛋白质。CDC48 与 SUMO 化的 Rad52 相关联，Rad52 是一种在染色质上组装 Rad51 重组酶的因子。通过作用于 Rad52-Rad51 复合物，CDC48 抑制它们的物理相互作用，并将蛋白质从 DNA 上置换下来。遗传干扰 SUMO 靶向或分拣酶活性会导致自发重组率增加，同时伴随着酵母和哺乳动物细胞中异常的体内 Rad51 焦点形成。因此，我们的数据表明，SUMO 靶向的 CDC48 通过平衡 Rad52 的活性来限制重组酶 Rad51。我们提出，CDC48 通过与具有泛素和 SUMO 亲和力的共因子结合的能力，将两种蛋白降解或其他调节目的的修饰途径联系起来。
