Chromosome Biology Unit, Danish Cancer Society Research Center and Center for Genotoxic Stress Research, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Cell. 2012 Aug 17;150(4):697-709. doi: 10.1016/j.cell.2012.06.039. Epub 2012 Aug 9.
Histone ubiquitylation is a prominent response to DNA double-strand breaks (DSBs), but how these modifications are confined to DNA lesions is not understood. Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. Thus, regulatory and proteolytic ubiquitylations are wired in a self-limiting circuit that promotes histone ubiquitylation near the DNA lesions but at the same time counteracts its excessive spreading to undamaged chromosomes. We provide evidence that this mechanism is vital for the homeostasis of ubiquitin-controlled events after DNA breakage and can be subverted during tumorigenesis.
组蛋白泛素化是对 DNA 双链断裂 (DSB) 的主要反应，但这些修饰如何局限于 DNA 损伤尚不清楚。在这里，我们表明，TRIP12 和 UBR5 这两种 HECT 结构域泛素 E3 连接酶控制着 RNF168 的积累，RNF168 是一种途径的限速组成部分，该途径在 DNA 断裂后泛素化组蛋白。我们发现，RNF168 可以通过增加 DSB 的数量而饱和。TRIP12 和 UBR5 的耗竭允许 RNF168 积累到超生理水平，随后大量的泛素缀合物扩散，以及大量的泛素调节的基因组看护者如 53BP1 和 BRCA1 的过度积累。因此，调节和蛋白水解泛素化被连接在一个自我限制的电路中，该电路促进了 DNA 损伤附近的组蛋白泛素化，但同时又阻止了其过度扩散到未受损的染色体上。我们提供的证据表明，这种机制对于 DNA 断裂后泛素控制事件的动态平衡至关重要，并且在肿瘤发生过程中可能被颠覆。
