USP1 deubiquitinase maintains phosphorylated CHK1 by limiting its DDB1-dependent degradation.
USP1 deubiquitinase maintains phosphorylated CHK1 by limiting its DDB1-dependent degradation.
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DOI：
10.1093/hmg/ddr103
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发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Rosselli F
中科院分区：
文献类型：
--
作者：
Guervilly JH;Renaud E;Takata M;Rosselli F
遗传稳定性的维持取决于细胞周期检查点和 DNA 修复途径的微调启动和终止。在这里，我们描述了一种调节检查点激酶 1 (CHK1) 活性的新途径，CHK1 是控制检查点和 DNA 修复的关键元件。我们发现，泛素特异性肽酶 1 (USP1) 去泛素酶参与维持 CHK1 的总水平和磷酸化水平，以应对基因毒性应激。我们确定，USP1 缺失会以单泛素化范可尼贫血、互补组 D2 (FANCD2) 依赖性和非依赖性方式刺激磷酸化 CHK1 的损伤特异性 DNA 结合蛋白 1 依赖性降解。我们的数据支持 CHK1 激活检查点、DNA 修复和增殖细胞核抗原以及 FANCD2 单泛素化的回路的存在。后两个事件反过来通过负反馈抑制关闭激活的 CHK1，从而导致 DNA 损伤反应的下调。该通路在癌症易发性疾病范可尼贫血 (FA) 中受到损害，可能导致 FA 患者的细胞对 DNA 损伤和该综合征的临床表型过敏；它还可能代表改善患者护理和开发新癌症疗法的药理学目标。
The maintenance of genetic stability depends on the fine-tuned initiation and termination of pathways involved in cell cycle checkpoints and DNA repair. Here, we describe a new pathway that regulates checkpoint kinase 1 (CHK1) activity, a key element controlling both checkpoints and DNA repair. We show that the ubiquitin-specific peptidase 1 (USP1) deubiquitinase participates in the maintenance of both total and phosphorylated levels of CHK1 in response to genotoxic stress. We establish that USP1 depletion stimulates the damage-specific DNA-binding protein 1-dependent degradation of phosphorylated CHK1 in both a monoubiquitinylated Fanconi anaemia, complementation group D2 (FANCD2)-dependent and -independent manner. Our data support the existence of a circuit in which CHK1 activates checkpoints, DNA repair and proliferating cell nuclear antigen and FANCD2 monoubiquitinylation. The latter two events, in turn, switch off activated CHK1 by negative feedback inhibition, which contributes to the downregulation of the DNA damage response. This pathway, which is compromised in the cancer-prone disease Fanconi anaemia (FA), likely contributes to the hypersensitivity of cells from FA patients to DNA damage and to the clinical phenotype of the syndrome; it may also represent a pharmacological target to improve patient care and develop new cancer therapies.
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影响因子：
16
作者：
Ben-Yehoyada M;Wang LC;Kozekov ID;Rizzo CJ;Gottesman ME;Gautier J
通讯作者：
Gautier J
USP7抵消了SCFBETATATRCP-，但不反对APCCDH1介导的链蛋白蛋白水解。
DOI：
10.1083/jcb.200807137
发表时间：
2009-01-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Faustrup H;Bekker-Jensen S;Bartek J;Lukas J;Mailand N
通讯作者：
Mailand N
影响因子：
16
作者：
Collis, Spencer J.;Ciccia, Alberto;Boulton, Simon J.
通讯作者：
Boulton, Simon J.
影响因子：
21.3
作者：
Collis, Spencer J.;Barber, Louise J.;Boulton, Simon J.
通讯作者：
Boulton, Simon J.
影响因子：
11.4
作者：
Hirano, S;Yamamoto, K;Takata, M
通讯作者：
Takata, M