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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.

Pubmed ID: 16901786

Authors

  • Zhang D
  • Zaugg K
  • Mak TW
  • Elledge SJ

Journal

Cell

Publication Data

August 11, 2006

Associated Grants

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

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
  • Ubiquitin
  • Ubiquitin Thiolesterase