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Stochastic transcription in the p53-mediated response to DNA damage is modulated by burst frequency.

Friedrich, Dhana and Friedel, Laura and Finzel, Ana and Herrmann, Andreas and Preibisch, Stephan and Loewer, Alexander (2019):
Stochastic transcription in the p53-mediated response to DNA damage is modulated by burst frequency.
In: Molecular systems biology, 15 (12), pp. e9068. ISSN 1744-4292,
DOI: 10.15252/msb.20199068,
[Article]

Abstract

Discontinuous transcription has been described for different mammalian cell lines and numerous promoters. However, our knowledge of how the activity of individual promoters is adjusted by dynamic signaling inputs from transcription factors is limited. To address this question, we characterized the activity of selected target genes that are regulated by pulsatile accumulation of the tumor suppressor p53 in response to ionizing radiation. We performed time-resolved measurements of gene expression at the single-cell level by smFISH and used the resulting data to inform a mathematical model of promoter activity. We found that p53 target promoters are regulated by frequency modulation of stochastic bursting and can be grouped along three archetypes of gene expression. The occurrence of these archetypes cannot solely be explained by nuclear p53 abundance or promoter binding of total p53. Instead, we provide evidence that the time-varying acetylation state of p53's C-terminal lysine residues is critical for gene-specific regulation of stochastic bursting.

Item Type: Article
Erschienen: 2019
Creators: Friedrich, Dhana and Friedel, Laura and Finzel, Ana and Herrmann, Andreas and Preibisch, Stephan and Loewer, Alexander
Title: Stochastic transcription in the p53-mediated response to DNA damage is modulated by burst frequency.
Language: English
Abstract:

Discontinuous transcription has been described for different mammalian cell lines and numerous promoters. However, our knowledge of how the activity of individual promoters is adjusted by dynamic signaling inputs from transcription factors is limited. To address this question, we characterized the activity of selected target genes that are regulated by pulsatile accumulation of the tumor suppressor p53 in response to ionizing radiation. We performed time-resolved measurements of gene expression at the single-cell level by smFISH and used the resulting data to inform a mathematical model of promoter activity. We found that p53 target promoters are regulated by frequency modulation of stochastic bursting and can be grouped along three archetypes of gene expression. The occurrence of these archetypes cannot solely be explained by nuclear p53 abundance or promoter binding of total p53. Instead, we provide evidence that the time-varying acetylation state of p53's C-terminal lysine residues is critical for gene-specific regulation of stochastic bursting.

Journal or Publication Title: Molecular systems biology
Journal volume: 15
Number: 12
Divisions: 10 Department of Biology
10 Department of Biology > Systems Biology of the Stress Response
Date Deposited: 06 Jan 2020 11:53
DOI: 10.15252/msb.20199068
Identification Number: pmid:31885199
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