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Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10364-9. Epub 2007 Jun 11.

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

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  • 1Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.

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.

PMID:
17563356
[PubMed - indexed for MEDLINE]
PMCID:
PMC1965519
Free PMC Article

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