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

Cell. 2006 Aug 11;126(3):529-42. doi: 10.1016/j.cell.2006.06.039.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • CLSPN protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • MDC1 protein, human
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • TOPBP1 protein, human
  • TP53BP1 protein, human
  • Trans-Activators
  • Tumor Suppressor Protein p53
  • Tumor Suppressor p53-Binding Protein 1
  • USP28 protein, human
  • Ubiquitin
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endopeptidases
  • Ubiquitin Thiolesterase