Journal
MOLECULAR CELL
Volume 64, Issue 1, Pages 51-64Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.08.002
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Funding
- Cancer Research UK (CRUK) [C52690/A19270]
- CRUK [C5255/A18085]
- Wellcome Trust [090532/Z/09/Z]
- Nuffield Department of Medicine
- European Commission [H2020-MSCA-IF-2014-656357]
- Cancer Research UK [19270] Funding Source: researchfish
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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 that 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 provide 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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