Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.molcel.2016.08.002

Type

Journal article

Journal

Mol Cell

Publication Date

06/10/2016

Volume

64

Pages

51 - 64

Keywords

Bacterial Proteins, Base Sequence, Binding Sites, Clustered Regularly Interspaced Short Palindromic Repeats, DNA Breaks, Double-Stranded, DNA Repair, Endonucleases, Gamma Rays, Gene Editing, Gene Expression Regulation, Humans, MCF-7 Cells, Promoter Regions, Genetic, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Multimerization, RNA, Guide, Signal Transduction, Tumor Suppressor Protein p53, Tumor Suppressor p53-Binding Protein 1, Ubiquitin Thiolesterase