53BP1 Integrates DNA Repair and p53-Dependent Cell Fate Decisions via Distinct Mechanisms

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 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.

Graphical Abstract

Highlights

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  53BP1 enhances genome-wide p53-dependent transcriptional responses

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  53BP1’s DNA repair and p53-regulatory roles are distinct and separable

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  Regulation requires 53BP1 oligomerization and BRCT domain interactions with p53 and USP28

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  53BP1-USP28 complexes function to stimulate p53 DNA-binding activity

Abstract

53BP1 was first identified as p53 binding protein 1, yet the function of the p53-53BP1 interaction was unclear. Cuella-Martin et al. show that 53BP1 bridges interactions between p53 and the deubiquitinating enzyme USP28, promoting p53-DNA interactions to globally enhance p53-dependent transcriptional programs.