Checkpoint kinases regulate a global network of transcription factors in response to DNA damage

Cell Rep. 2013 Jul 11;4(1):174-88. doi: 10.1016/j.celrep.2013.05.041. Epub 2013 Jun 27.

Abstract

DNA damage activates checkpoint kinases that induce several downstream events, including widespread changes in transcription. However, the specific connections between the checkpoint kinases and downstream transcription factors (TFs) are not well understood. Here, we integrate kinase mutant expression profiles, transcriptional regulatory interactions, and phosphoproteomics to map kinases and downstream TFs to transcriptional regulatory networks. Specifically, we investigate the role of the Saccharomyces cerevisiae checkpoint kinases (Mec1, Tel1, Chk1, Rad53, and Dun1) in the transcriptional response to DNA damage caused by methyl methanesulfonate. The result is a global kinase-TF regulatory network in which Mec1 and Tel1 signal through Rad53 to synergistically regulate the expression of more than 600 genes. This network involves at least nine TFs, many of which have Rad53-dependent phosphorylation sites, as regulators of checkpoint-kinase-dependent genes. We also identify a major DNA damage-induced transcriptional network that regulates stress response genes independently of the checkpoint kinases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2 / genetics*
  • Checkpoint Kinase 2 / metabolism
  • DNA Damage*
  • DNA, Fungal / metabolism
  • Gene Expression Regulation, Fungal*
  • Gene Regulatory Networks
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic

Substances

  • Cell Cycle Proteins
  • DNA, Fungal
  • Intracellular Signaling Peptides and Proteins
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • Protein Kinases
  • DUN1 protein, S cerevisiae
  • Checkpoint Kinase 2
  • Checkpoint Kinase 1
  • MEC1 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases
  • TEL1 protein, S cerevisiae
  • RAD53 protein, S cerevisiae