Genome Instability and Carcinogenesis UPR3081 CNRS, IGC, IMM, 31 chemin Joseph Aiguier, 13402 Marseille, France.
Hum Mol Genet. 2011 Jun 1;20(11):2171-81. doi: 10.1093/hmg/ddr103. Epub 2011 Mar 9.
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.
遗传稳定性的维持依赖于细胞周期检查点和 DNA 修复途径的精细启动和终止。在这里，我们描述了一条新的通路，该通路调节检查点激酶 1（CHK1）的活性，这是控制检查点和 DNA 修复的关键因素。我们表明，泛素特异性肽酶 1（USP1）去泛素酶参与应对遗传毒性应激时总 CHK1 和磷酸化 CHK1 水平的维持。我们确定 USP1 耗竭以依赖和不依赖单泛素化范可尼贫血互补组 D2（FANCD2）的方式刺激损伤特异性 DNA 结合蛋白 1 依赖性磷酸化 CHK1 的降解。我们的数据支持这样一个回路的存在，即 CHK1 激活检查点、DNA 修复和增殖细胞核抗原以及 FANCD2 单泛素化。后两个事件反过来通过负反馈抑制关闭激活的 CHK1，这有助于下调 DNA 损伤反应。这条通路在易患癌症的范可尼贫血症（FA）中受到损害，可能导致 FA 患者的细胞对 DNA 损伤的敏感性增加，并导致该综合征的临床表型；它也可能代表一种药理学靶点，以改善患者护理并开发新的癌症疗法。
