HPF1/C4orf27 Is a PARP-1-Interacting Protein that Regulates PARP-1 ADP-Ribosylation Activity.
HPF1/C4orf27 Is a PARP-1-Interacting Protein that Regulates PARP-1 ADP-Ribosylation Activity.
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DOI：
10.1016/j.molcel.2016.03.008
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发表时间：
2016-05-05
期刊：
影响因子：
16
通讯作者：
Ahel I
中科院分区：
文献类型：
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作者：
Gibbs-Seymour I;Fontana P;Rack JGM;Ahel I
我们报告了组蛋白PAR化因子1（HPF 1;也称为C4 orf 27）作为DNA损伤反应中ADP-核糖基化信号传导的调节因子的鉴定。HPF 1/C4 orf 27在细胞中与PARP-1形成稳健的蛋白质复合物，并以PARP-1依赖性方式募集至DNA损伤，但不依赖于PARP-1催化ADP-核糖基化活性。在功能上，HPF 1促进PARP-1依赖性的组蛋白反式ADP核糖基化，并限制DNA损伤诱导的PARP-1超自修饰。缺乏HPF 1的人类细胞表现出对DNA损伤剂和PARP抑制的敏感性，从而表明HPF 1在基因组维持和调节PARP抑制剂的功效中具有重要作用。总的来说，我们的研究结果表明，PARP-1依赖的ADP-核糖基化信号转导的基本步骤是如何调节的，并表明HPF 1在组蛋白ADP-核糖基化和PARP-1自动修饰的十字路口发挥作用。组蛋白PARylation factor 1（HPF 1）是DNA损伤反应的一个组分，HPF 1通过PARP-1催化结构域与细胞中的PARP-1相互作用。HPF 1的缺失使人类细胞对DNA损伤剂敏感，PARP抑制HPF 1促进组蛋白的PARP-1依赖性ADP-核糖基化。鉴定组蛋白PAR化因子1（HPF 1;也称为C4 orf 27）作为DNA损伤反应的PARP-1相互作用组分。人类细胞中HPF 1的缺失使细胞对DNA损伤剂和PARP抑制剂敏感。在功能上，HPF 1促进组蛋白的PARP-1依赖性ADP-核糖基化，以确保基因组稳定性。
We report the identification of histone PARylation factor 1 (HPF1; also known as C4orf27) as a regulator of ADP-ribosylation signaling in the DNA damage response. HPF1/C4orf27 forms a robust protein complex with PARP-1 in cells and is recruited to DNA lesions in a PARP-1-dependent manner, but independently of PARP-1 catalytic ADP-ribosylation activity. Functionally, HPF1 promotes PARP-1-dependent in trans ADP-ribosylation of histones and limits DNA damage-induced hyper-automodification of PARP-1. Human cells lacking HPF1 exhibit sensitivity to DNA damaging agents and PARP inhibition, thereby suggesting an important role for HPF1 in genome maintenance and regulating the efficacy of PARP inhibitors. Collectively, our results demonstrate how a fundamental step in PARP-1-dependent ADP-ribosylation signaling is regulated and suggest that HPF1 functions at the crossroads of histone ADP-ribosylation and PARP-1 automodification. Histone PARylation factor 1 (HPF1) is a component of the DNA damage response HPF1 interacts with PARP-1 in cells via the PARP-1 catalytic domain Loss of HPF1 sensitizes human cells to DNA damaging agents and PARP inhibition HPF1 promotes PARP-1-dependent ADP-ribosylation of histones Gibbs-Seymour et al. identify histone PARylation factor 1 (HPF1; also known as C4orf27) as a PARP-1-interacting component of the DNA damage response. Deletion of HPF1 in human cells sensitizes cells to DNA damaging agents and to PARP inhibition. Functionally, HPF1 promotes PARP-1-dependent ADP-ribosylation of histones to ensure genome stability.