title: 53BP1 Integrates DNA Repair and p53-Dependent Cell Fate Decisions via Distinct Mechanisms.
abstract: 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.
authors.affiliation: Chromatin and Genome Integrity Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Raquel
authors.initials: R
authors.lastname: Cuella-Martin
authors.affiliation: Chromatin and Genome Integrity Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Catarina
authors.initials: C
authors.lastname: Oliveira
authors.affiliation: Bioinformatics and Statistical Genetics Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Lockstone
authors.affiliation: Chromatin and Genome Integrity Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Snellenberg
authors.affiliation: Chromatin and Genome Integrity Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Grolmusova
authors.affiliation: Chromatin and Genome Integrity Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. Electronic address: rchapman@well.ox.ac.uk.
authors.forename: J Ross
authors.initials: JR
authors.lastname: Chapman
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D000076987:CRISPR-Associated Protein 9; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays; D000072669:Gene Editing; D005786:Gene Expression Regulation; D006801:Humans; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000094704:RNA, Guide, CRISPR-Cas Systems
chemical_list: D001426:Bacterial Proteins; D000076987:CRISPR-Associated Protein 9; D004720:Endonucleases; D016159:Tumor Suppressor Protein p53; D000071857:Tumor Suppressor p53-Binding Protein 1; D043222:Ubiquitin Thiolesterase; D000094704:RNA, Guide, CRISPR-Cas Systems; C498301:TP53BP1 protein, human; C442902:USP28 protein, human; C000606107:Cas9 endonuclease Streptococcus pyogenes