TY - JOUR
T1 - Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage
AU - Jaehnig, Eric J.
AU - Kuo, Dwight
AU - Hombauer, Hans
AU - Ideker, Trey G.
AU - Kolodner, Richard D.
N1 - Funding Information:
The authors would like to thank R.D.K. and T.G.I. lab members for helpful discussions and the Huilin Zhou lab for help with the mass spectrometry experiments. This work was supported by NIH grants F32 GM086899 (to E.J.J.), ES014811 (to T.G.I.), GM26017 (to R.D.K.), and GM085764 (to T.G.I.).
PY - 2013/7/11
Y1 - 2013/7/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2013.05.041
DO - 10.1016/j.celrep.2013.05.041
M3 - Article
C2 - 23810556
AN - SCOPUS:84892431829
SN - 2211-1247
VL - 4
SP - 174
EP - 188
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -