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Status |
Public on Aug 18, 2016 |
Title |
53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
The tumor suppressor protein 53BP1, a pivotal regulator of DNA double-strand break (DSB) repair, was first identified as a p53-interacting protein over two decades ago, however its direct contributions to p53-dependent cellular activities remain undefined. Here, we reveal 53BP1 stimulates genome-wide p53-dependent gene transactivation and repression events in response to ionizing radiation (IR) and synthetic p53 activation. 53BP1-dependent p53 modulation requires both auto-oligomerization and tandem-BRCT domain mediated bivalent interactions with p53 and the ubiquitin-specific protease USP28. Loss of these activities results in inefficient p53-dependent cell-cycle checkpoint and exit responses. Furthermore, we demonstrate 53BP1-USP28 cooperation to be essential for normal p53-promoter element interactions and gene transactivation-associated events, yet dispensable for 53BP1-dependent DSB repair regulation. Collectively, our data provides a mechanistic explanation for 53BP1-p53 cooperation in controlling anti-tumorigenic cell fate decisions, and reveal these activities to be distinct and separable from 53BP1’s regulation of DNA double-strand break repair pathway choice.
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Overall design |
We evaluated the transcriptional profiles of two 53BP1Δ cell lines and included a positive (WT) and a negative (p53Δ) controls. These cell lines were treated with Nutlin-3, ionising radiation or mock treated. Three independent replicates were included for each independent condition generating a total of 36 samples.
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Contributor(s) |
Cuella-Martin R, Oliveira C, Lockstone HE, Snellenberg S, Gromulsova N, Chapman JR |
Citation(s) |
27546791 |
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Submission date |
Jul 29, 2016 |
Last update date |
May 15, 2019 |
Contact name |
Jonathan Ross Chapman |
E-mail(s) |
rchapman@well.ox.ac.uk
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Organization name |
Wellcome Trust Centre for Human Genetics
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Department |
Nuffield Department of Medicine (University of Oxford)
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Street address |
Roosevelt Drive
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City |
Oxford |
ZIP/Postal code |
OX3 7BN |
Country |
United Kingdom |
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Platforms (1) |
GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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Samples (36)
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Relations |
BioProject |
PRJNA335834 |
SRA |
SRP080321 |