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The deubiquitylation enzyme USP7/HAUSP plays a major role in regulating genome stability and cancer prevention by controlling the key proteins involved in the DNA damage response. Despite this important role in controlling other proteins, USP7 itself has not been recognized as a target for regulation. Here, we report that USP7 regulation plays a central role in DNA damage signal transmission. We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53. After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. Our findings provide a quantitative transmission mechanism of the DNA damage signal to coordinate a p53-dependent DNA damage response.

Original publication

DOI

10.1016/j.molcel.2012.01.021

Type

Journal article

Journal

Molecular cell

Publication Date

03/2012

Volume

45

Pages

801 - 813

Addresses

Department of Oncology, Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, UK.

Keywords

Hela Cells, Humans, DNA Damage, Ubiquitin Thiolesterase, Protein-Serine-Threonine Kinases, Casein Kinase II, Serine, Cell Cycle Proteins, DNA-Binding Proteins, Tumor Suppressor Proteins, Signal Transduction, Down-Regulation, Amino Acid Sequence, Phosphorylation, Radiation, Ionizing, Molecular Sequence Data, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2, Phosphoprotein Phosphatases, Cell Cycle Checkpoints, Ataxia Telangiectasia Mutated Proteins, Protein Phosphatase 2C, Ubiquitin-Specific Peptidase 7