Mapping the DNA Damage Response
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Transcript of Mapping the DNA Damage Response
![Page 1: Mapping the DNA Damage Response](https://reader033.fdocuments.in/reader033/viewer/2022051018/56812a8b550346895d8e31d7/html5/thumbnails/1.jpg)
Case study reveals transcription factor (TF) modules, dynamic TF binding and an expanded role for cell cycle regulators
Mapping the DNA Damage Response
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Overview
• Experimental factors and selection– Multiple criteria used
• ChIP-on-chip– Differential binding analysis
• Gene expression of TF-deletion mutants– Clustering analysis– Deletion-buffering analysis
• Data integration and pathway reconstruction
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Overview of the approach
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Overview of the approach
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Overview of the approach
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Transcription factors that regulate DNA damage response
Activated regulatory network
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Transcription factors that regulate DNA damage response
TF knockout
“Deletion-buffered”
Activated regulatory network
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Growth phenotype in MMS: mutants that display relative growth inhibition
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Truncated Product Method (TPM): determine condition dependent binding
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ChIP-chip of 30 TFs before and after DNA damage
YPD MMS+/-MMS
TPM
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ChIP-chip Data Summary
Workman CT, Mak HC, McCuine S, Tagne JB, Agarwal M, Ozier O, Begley TJ, Samson LD, Ideker T. A systems approach to mapping DNA damage response pathways. Science. 2006 May 19;312(5776):1054-9.
TFs may regulate different genes (bind different promoters) under different conditions.
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Promoter regions analysisChIP-chip and DNA-Motif
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TF-Knockout expression profiles:(look much like wild-type)
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Environmental “epistasis analysis”:(deletion-buffering)
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Deletion-buffering analysis
Bayesian Score
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Deletion-buffering examples
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RNR Genes are repressed by Rfx1p
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Sensitive TFs are required for a greater number of damage responsive genes
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Integrated model(regulatory paths explaining buffered genes)
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Pathway reconstruction
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Pathway reconstruction
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Pathway reconstruction
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Integrated direct and indirect regulatory pathways (chIP-chip, prot-prot) that explain deletion-buffering relationships
Workman CT, Mak HC, McCuine S, Tagne JB, Agarwal M, Ozier O, Begley TJ, Samson LD, Ideker T. A systems approach to mapping DNA damage response pathways. Science. 2006 May 19;312(5776):1054-9.
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Summary
• “Sensitive” TFs control more of the DNA damage response than non-sensitive TFs
• Regulatory networks are highly interconnected
• Transcriptional regulation of important DNA damage checkpoint kinases are observed
• Measuring differential TF-binding is difficult