USP1 deubiquitinase maintains phosphorylated CHK1 by limiting its DDB1-dependent degradation

Genome Instability and Carcinogenesis UPR3081 CNRS, IGC, IMM, 31 chemin Joseph Aiguier, 13402 Marseille, France.
Human Molecular Genetics (Impact Factor: 6.39). 03/2011; 20(11):2171-81. DOI: 10.1093/hmg/ddr103
Source: PubMed


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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Available from: Filippo Rosselli, Oct 08, 2015
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    • "FANC pathway downregulation or deficiency was correlated with decreased levels of p-RPA32, with decreased frequency of p-RPA32 foci and with enhanced γH2AX accumulation (Figures 3B, 3C and S3A). As previously reported [20], [21], CHK1 was hyperphosphorylated in FANC-deficient cells (Figure 3C). Thus, the deficit in RPA phosphorylation that occurs in these cells cannot merely be ascribed to a defect in ATR activity; it is more likely to represent the consequence of the presence of fewer stretches of ssDNA. "
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    • "In the lung, Tnc appears at the epithelial-mesenchymal interface during branching morphogenesis where it may promote airway branching [30], [31]. Usp1 depletion impacts the stability and phosphorylation of Chk1 which is a cell cycle regulated and DNA damage checkpoint protein [32]. Given their known biological function, the downregulated expression of these genes is consistent with our observation of impaired BASC proliferation induced by c-Myc depletion. "
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