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

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Apoptosis Regulatory Proteins, Carrier Proteins, Cell Transformation, Neoplastic, 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, Ubiquitin, Ubiquitin Thiolesterase
Cell
Date: Aug. 11, 2006
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