Role of Cdc48/p97 as a SUMO-targeted segregase curbing Rad51-Rad52 interaction
Role of Cdc48/p97 as a SUMO-targeted segregase curbing Rad51-Rad52 interaction
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DOI：
10.1038/ncb2729
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发表时间：
2013-05-01
影响因子：
21.3
通讯作者：
Jentsch, Stefan
中科院分区：
文献类型：
--
作者：
Bergink, Steven;Ammon, Tim;Jentsch, Stefan
Cdc48（也称为 p97）是一种保守的分子伴侣样 ATP 酶，在泛素系统中发挥着战略作用(1-3)。在 ATP 驱动的构象变化 (4) 的支持下，Cdc48 通过将泛素化蛋白质从其环境中移出而充当分离酶 (1,2,5)。 Ufd1 是 Cdc48 的已知辅助因子，也结合 SUMO（参考文献 6），但 SUMO 化蛋白是否也受到 Cdc48 分离酶活性的影响以及这些底物是什么仍然未知。在这里，我们表明 Cdc48 及其辅因子 Ufd1 以 SUMO 方式靶向参与 DNA 双链断裂修复的蛋白质。 Cdc48 与 SUMOylated Rad52 结合，后者是在染色质上组装 Rad51 重组酶的因子。通过作用于 Rad52-Rad51 复合物，Cdc48 抑制了它们的物理相互作用并取代了 DNA 中的蛋白质。对 SUMO 靶向或分离酶活性进行遗传干扰会导致自发重组率增加，并伴有酵母和哺乳动物细胞体内 Rad51 焦点形成异常。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。我们认为，Cdc48 通过其与对泛素和 SUMO 有亲和力的辅因子关联的能力，连接了两种修饰途径以实现蛋白质降解或其他调节目的。
Cdc48 (also known as p97), a conserved chaperone-like ATPase, plays a strategic role in the ubiquitin system(1-3). Empowered by ATP-driven conformational changes(4), Cdc48 acts as a segregase by dislodging ubiquitylated proteins from their environment(1,2,5). 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.