Abstract PR20: A 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms

The tumor suppressor protein 53BP1 was first identified as a p53-interacting protein over two decades ago, however its direct contribution to p53-dependent cellular activities has remained enigmatic. Having reinvestigated the link between 53BP1 and p53, we now show 53BP1 plays an important role in directly stimulating genome-wide p53-dependent gene transactivation and repression events in response to ionizing radiation (IR) and synthetic p53 activation. We have also fine-mapped the domains in 53BP1 that modulate p53 activity and reveal it requires both auto-oligomerization and its tandem-BRCT domain-mediated bivalent interactions with p53 and the ubiquitin-specific protease USP28. Loss of 53BP1 or USP28 catalytic activities results in inefficient p53-dependent cell-cycle checkpoint and exit responses. Mechanistically, we show 53BP1-USP28 cooperation to be essential for stimulating normal p53-promoter element interactions and downstream gene transactivation-associated events, yet dispensable for 53BP1-dependent DSB repair regulation. Collectively, our data indicate a upstream role for 53BP1-USP28 complexes in priming p53's transcriptional potential, providing a mechanistic explanation for 53BP1-p53 cooperation in controlling anti-tumorigenic cell-fate decisions. Moreover, we reveal these activities to be distinct and separable from 53BP1's regulation of DNA double-strand break repair pathway choice, and establish the prime function for the 53BP1 BRCT domain and its interaction...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: DNA Damage Signaling: Oral Presentations - Proffered Abstracts Source Type: research