TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes
TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes
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DOI：
10.1016/j.cell.2012.06.039
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发表时间：
2012-08-17
期刊：
影响因子：
64.5
通讯作者：
Lukas, Claudia
中科院分区：
文献类型：
--
作者：
Gudjonsson, Thorkell;Altmeyer, Matthias;Lukas, Claudia
组蛋白泛素化是对DNA双链断裂（DSBs）的重要反应，但这些修饰如何局限于DNA损伤尚不清楚。在这里，我们发现TRIP12和UBR5，两个HECT结构域E3泛素连接酶，控制RNF168的积累，RNF168是DNA断裂后组蛋白泛素化途径的限速组分。我们发现RNF168可以通过增加dsb的数量而饱和。TRIP12和UBR5的缺失使RNF168的积累达到超生理水平，随后泛素偶联物大量扩散，泛素调控的基因组看护物如53BP1和BRCA1的过度积累。因此，调节和蛋白水解泛素化在一个自我限制的电路中连接，促进DNA损伤附近的组蛋白泛素化，但同时抵消其过度扩散到未受损的染色体。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稳态至关重要，并且可以在肿瘤发生过程中被破坏。
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 supra-physiological 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.