Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage
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 express...
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doaj-41d04e34ebda42168b3913bb56be7ccf2020-11-24T23:54:39ZengElsevierCell Reports2211-12472013-07-014117418810.1016/j.celrep.2013.05.041Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA DamageEric J. Jaehnig0Dwight Kuo1Hans Hombauer2Trey G. Ideker3Richard D. Kolodner4Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USADepartment of Bioengineering, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USALudwig Institute for Cancer Research, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USADepartment of Medicine, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USALudwig Institute for Cancer Research, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA 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. http://www.sciencedirect.com/science/article/pii/S221112471300274X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Eric J. Jaehnig Dwight Kuo Hans Hombauer Trey G. Ideker Richard D. Kolodner |
spellingShingle |
Eric J. Jaehnig Dwight Kuo Hans Hombauer Trey G. Ideker Richard D. Kolodner Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage Cell Reports |
author_facet |
Eric J. Jaehnig Dwight Kuo Hans Hombauer Trey G. Ideker Richard D. Kolodner |
author_sort |
Eric J. Jaehnig |
title |
Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage |
title_short |
Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage |
title_full |
Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage |
title_fullStr |
Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage |
title_full_unstemmed |
Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage |
title_sort |
checkpoint kinases regulate a global network of transcription factors in response to dna damage |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2013-07-01 |
description |
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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url |
http://www.sciencedirect.com/science/article/pii/S221112471300274X |
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