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.
Mesh Terms:
Amino Acid Sequence, Antibodies, Phospho-Specific, 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
J. Biol. Chem.
Date: Jun. 15, 2007
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