Jun 15, 2007

Proteome-wide identification of in vivo targets of DNA damage checkpoint kinases

Proceedings of the National Academy of Sciences of the United States of America
Marcus B SmolkaHuilin Zhou

Abstract

Understanding the role of DNA damage checkpoint kinases in the cellular response to genotoxic stress requires the knowledge of their substrates. Here, we report the use of quantitative phosphoproteomics to identify in vivo kinase substrates of the yeast DNA damage checkpoint kinases Mec1, Tel1, and Rad53 (orthologs of human ATR, ATM, and CHK2, respectively). By analyzing 2,689 phosphorylation sites in wild-type and various kinase-null cells, 62 phosphorylation sites from 55 proteins were found to be controlled by the DNA damage checkpoint. Examination of the dependency of each phosphorylation on Mec1 and Tel1 or Rad53, combined with sequence and biochemical analysis, revealed that many of the identified targets are likely direct substrates of these kinases. In addition to several known targets, 50 previously undescribed targets of the DNA damage checkpoint were identified, suggesting that a wide range of cellular processes is likely regulated by Mec1, Tel1, and Rad53.

  • References44
  • Citations209

References

Mentioned in this Paper

Saccharomyces cerevisiae Proteins
CHEK2 wt Allele
CHEK2 gene
Cell Cycle Proteins
Intracellular Signaling Proteins
Response to DNA Damage Stimulus
Protein Phosphorylation
Null Cell
Tandem Mass Spectrometry
Dimethylsulfonate

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