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A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response.

Cell | Aug 11, 2006

The Chk2-p53-PUMA pathway is a major regulator of DNA-damage-induced apoptosis in response to double-strand breaks in vivo. Through analysis of 53BP1 complexes we have discovered a new ubiquitin protease, USP28, which regulates this pathway. Using a human cell line that faithfully recapitulated the Chk2-p53-PUMA pathway, we show that USP28 is required to stabilize Chk2 and 53BP1 in response to DNA damage. In this cell line, both USP28 and Chk2 are required for DNA-damage-induced apoptosis, and they accomplish this in part through regulation of the p53 induction of proapoptotic genes like PUMA. Our studies implicate DNA-damage-induced ubiquitination and deubiquitination as a major regulator of the DNA-damage response for Chk2, 53BP1, and a number of other proteins in the DNA-damage checkpoint pathway, including several mediators, such as Mdc1, Claspin, and TopBP1.

Pubmed ID: 16901786 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Animals | Apoptosis | Apoptosis Regulatory Proteins | Carrier Proteins | Cell Transformation, Neoplastic | Checkpoint Kinase 2 | DNA Damage | DNA-Binding Proteins | Endopeptidases | Fibroblasts | Genes, cdc | HeLa Cells | Humans | Intracellular Signaling Peptides and Proteins | Mice | Mice, Inbred C57BL | Nuclear Proteins | Phosphoproteins | Protein-Serine-Threonine Kinases | Proto-Oncogene Proteins | Signal Transduction | Trans-Activators | Tumor Suppressor Protein p53 | Tumor Suppressor p53-Binding Protein 1 | Ubiquitin | Ubiquitin Thiolesterase

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Associated grants

  • Agency: NCI NIH HHS, Id: T32 CA90221
  • Agency: NIAID NIH HHS, Id: U19 AI067751

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