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首页> 外文期刊>Genes and Development: a Journal Devoted to the Molecular Analysis of Gene Expression in Eukaryotes, Prokaryotes, and Viruses >SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage
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SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage

机译：SUMO靶向的泛素E3连接酶RNF4是人类细胞对DNA损伤的反应所必需的

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摘要

Here we demonstrate that RNF4, a highly conserved small ubiquitin-like modifier (SUMO)-targeted ubiquitin E3 ligase, plays a critical role in the response of mammalian cells to DNA damage. Human cells in which RNF4 expression was ablated by siRNA or chicken DT40 cells with a homozygous deletion of the RNF4 gene displayed increased sensitivity to DNA-damaging agents. Recruitment of RNF4 to double-strand breaks required its RING and SUMO interaction motif (SIM) domains and DNA damage factors such as NBS1, mediator of DNA damage checkpoint 1 (MDC1), RNF8, 53BP1, and BRCA1. In the absence of RNF4, these factors were still recruited to sites of DNA damage, but 53BP1, RNF8, and RNF168 displayed delayed clearance from such foci. SILAC-based proteomics of SUMO substrates revealed that MDC1 was SUMO-modified in response to ionizing radiation. As a consequence of SUMO modification, MDC1 recruited RNF4, which mediated ubiquitylation at the DNA damage site. Failure to recruit RNF4 resulted in defective loading of replication protein A (RPA) and Rad51 onto ssDNA. This appeared to be a consequence of reduced recruitment of the CtIP nuclease, resulting in inefficient end resection. Thus, RNF4 is a novel DNA damage-responsive protein that plays a role in homologous recombination and integrates SUMO modification and ubiquitin signaling in the cellular response to genotoxic stress.
机译：在这里，我们证明了RNF4，一种高度保守的小泛素样修饰物（SUMO）-靶向的泛素E3连接酶，在哺乳动物细胞对DNA损伤的反应中起关键作用。 siRNA或带有RNF4基因纯合缺失的鸡DT40细胞消融了RNF4表达的人细胞对DNA损伤剂的敏感性增加。 RNF4招募到双链断裂需要其RING和SUMO相互作用基序（SIM）域和DNA损伤因子，例如NBS1，DNA损伤检查点1（MDC1），RNF8、53BP1和BRCA1的介体。在缺乏RNF4的情况下，这些因子仍被募集到DNA损伤的位点，但是53BP1，RNF8和RNF168显示出从此类病灶清除的延迟。 SUMO底物的基于SILAC的蛋白质组学表明，MDC1被SUMO修饰以响应电离辐射。作为SUMO修饰的结果，MDC1募集了RNF4，它介导了DNA损伤位点的泛素化。无法募集RNF4导致复制蛋白A（RPA）和Rad51加载到ssDNA上的缺陷。这似乎是CtIP核酸酶募集减少的结果，导致末端切除效率低下。因此，RNF4是一种新型的DNA损伤反应蛋白，在同源重组中起作用，并且在细胞对遗传毒性胁迫的反应中整合了SUMO修饰和泛素信号传导。

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