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A proteomic analysis of ataxia telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) substrates identifies the ubiquitin-proteasome system as a regulator for DNA damage checkpoints.

ATM (ataxia telangiectasia-mutated) and ATR (ATM-Rad3-related) are proximal checkpoint kinases that regulate DNA damage response (DDR). Identification and characterization of ATM/ATR substrates hold the keys for the understanding of DDR. Few techniques are available to identify protein kinase substrates. Here, we screened for potential ATM/ATR substrates using phospho-specific antibodies against known ATM/ATR substrates. We identified proteins cross-reacting to phospho-specific antibodies in response to DNA damage by mass spectrometry. We validated a subset of the candidate substrates to be phosphorylated in an ATM/ATR-dependent manner in vivo. Combining with a functional checkpoint screen, we identified proteins that belong to the ubiquitin-proteasome system (UPS) to be required in mammalian DNA damage checkpoint control, particularly the G(1) cell cycle checkpoint, thus revealing protein ubiquitylation as an important regulatory mechanism downstream of ATM/ATR activation for checkpoint control.

Pubmed ID: 17478428

Authors

  • Mu JJ
  • Wang Y
  • Luo H
  • Leng M
  • Zhang J
  • Yang T
  • Besusso D
  • Jung SY
  • Qin J

Journal

The Journal of biological chemistry

Publication Data

June 15, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA84199
  • Agency: NCI NIH HHS, Id: CA98500

Mesh Terms

  • Amino Acid Sequence
  • Antibodies, Phospho-Specific
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins
  • HeLa Cells
  • Humans
  • Proteasome Endopeptidase Complex
  • Protein-Serine-Threonine Kinases
  • Proteome
  • Reproducibility of Results
  • Tumor Suppressor Proteins
  • Ubiquitin