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Short Title: 53bp1 supports p53-family transcriptional program

ABSTRACT: Understanding how molecular mechanisms regulate cell function in tissues requires approaches that link phenotypes to mechanisms across different spatial scales. Here, we present Automated Multimodal Multiplexed Microscopy for Image CytOmetry (A.M3.I.CO), a correlative imaging platform that combines multiscale resolution, from millimeters to nanometers, with automated workflows for high-throughput phenotypic profiling and targeted single-molecule analysis in-situ. Applying A.M3.I.CO, we observed that 53BP1 is recruited at transcribed p53-target genes independently of the activating stimuli, with evidence for a putative complex formation involving 53BP1, p53, and the basal transcription machinery, as also demonstrated by in-vivo observations in tumor models. This localization extends to p63- and p73-targeted transcription sites, suggesting a broader role for 53BP1 in participating to p53 family–dependent transcription. These findings extend genome surveillance pathways to transcriptional control for the execution of extremely different cell functions and establish A.M3.I.CO as a platform for spatially resolved functional analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE339307 | GEO | 2026/07/20

REPOSITORIES: GEO

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Short Title: 53bp1 supports p53-family transcriptional program

Project description:Short Title: 53bp1 supports p53-family transcriptional program

| PRJNA1498127 | ENA

53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms

Project description: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 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 provides 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.

2016-08-18 | GSE84986 | GEO

Phosphorylation of 53BP1 by ATM enforce neurodevelopmental programs in cortical organoids

Project description:53BP1 is a well-established DNA damage repair factor that has recently been shown to regulate gene expression and critically influence tumor suppression and neural development. For gene regulation, how 53BP1 is regulated remains unclear. Here, we showed that 53BP1-serine 25 phosphorylation by ATM is required for neural progenitor cell proliferation and neuronal differentiation in cortical organoids. 53BP1-serine 25 phosphorylation dynamics controls 53BP1 target genes for neuronal differentiation and function, cellular response to stress, and apoptosis. Beyond 53BP1, ATM is required for phosphorylation of factors in neuronal differentiation, cytoskeleton, p53 regulation, and ATM, BNDF, and WNT signaling pathways for cortical organoid differentiation. Overall, our data suggest that 53BP1 and ATM control key genetic programs required for human cortical development.

2024-08-11 | GSE231321 | GEO

NEAT1 Modulates the TIRR/53BP1 Complex to Maintain Genome Integrity

Project description:Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying NEAT1_1, the short isoform of the long noncoding RNA NEAT1, as the primary RNA partner. The high affinity of TIRR for NEAT1_1 is due to prevalent G-rich motifs in NEAT1_1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1's function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1’s function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting NEAT1_1 production. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases.

2024-09-04 | GSE276206 | GEO

Loss of KNTC1 Triggers a 53BP1 and USP28 Dependent Cell Cycle Arrest Without Prolonged Mitotic Delays

Project description:Accurate and efficient mitosis is the hallmark of animal cycling cells. While the spindle assembly checkpoint (SAC) ensures mitotic fidelity by delaying mitotic progression, a SAC-independent surveillance program is known to monitor the duration – without affecting the progression – of mitosis. This pathway, mediated by 53BP1, USP28, and p53, induces post-mitotic arrest in daughter cells following mitoses that exceed a defined temporal threshold. To uncover additional inputs into this pathway, we performed genome-wide CRISPR-Cas9 screens in wild-type, p53-/-, and USP28-/- human cells. Among genes selectively required in wild-type cells, we identified two components of the RZZ kinetochore complex—KNTC1 (ROD) and ZWILCH—as high-confidence hits. Remarkably, depleting KNTC1, which impaired SAC maintenance, triggered a robust 53BP1, USP28, and p53-dependent arrest without the characteristic mitotic delay. KNTC1-deficent cells could arrest following multiple, consecutive divisions with normal durations, and the last mitosis prior to arrest progressed no differently from the previous. Instead, loss of KNTC1 was found to trigger 53BP1-USP28-p53 complex formation soon after mitotic entry, an indication of pathway activation without prolonged mitosis. These findings suggest that the 53BP1–USP28–p53 surveillance pathway can monitor various mitotic anomalies to safeguard cell fitness.

2026-03-10 | GSE306237 | GEO

A damage independent role for 53BP1 that impacts break order and Igh architecture during CSR

Project description:During Class Switch Recombination (CSR) B cells replace the Igh CÎ¼/Î´ exons with another downstream constant region exon (CH), altering the antibody isotype. CSR occurs through the introduction of AID-mediated double strand break (DSBs) in switch regions and subsequent ligation of broken ends. Here we developed an assay to investigate the dynamics of DSB introduction in individual cells. We demonstrate that the upstream switch region SÎ¼ is always targeted first during recombination and that the mechanism underlying this control relies on 53BP1. Surprisingly, regulation of break order occurs through residual binding of 53BP1 to chromatin before the introduction of damage and independent of its established role in DNA repair. Using chromosome conformation capture we show that 53BP1 mediates changes in chromatin architecture that affect break order. Finally, our results explain how changes in Igh architecture in the absence of 53BP1 could promote inversional rearrangements that compromise CSR. High Resolution 4C was performed in resting and activated B cells using a bait on the EÎ¼ enhancer

2016-06-16 | E-GEOD-81180 | biostudies-arrayexpress

CRL3-GMCL1 mediates 53BP1 degradation, promoting evasion from mitotic surveillance upon paclitaxel treatment

Project description:The Mitotic Surveillance Pathway (MSP) is a critical quality control mechanism that monitors mitosis duration. Prolonged mitosis - caused by genomic defects, spindle errors, or anti-mitotic drugs such as paclitaxel - induces formation of the ternary -mitotic stopwatch- complex composed of 53BP1, USP28, and p53. This complex protects p53 from MDM2-mediated degradation, and its accumulation transmits a memory of the delayed mitosis to the daughter cells, where p53 signaling triggers cell cycle arrest and apoptosis. In Paclitaxel-resistant cancers, cells bypass the MSP, enabling unchecked proliferation and survival, though the underlying mechanisms remain unknown. Here, we identify CRL3GMCL1 as the ubiquitin ligase that targets 53BP1 for degradation during prolonged M phase. In cancers with high GMCL1 levels, the CRL3GMCL1-mediated degradation of 53BP1 prevents the formation of the mitotic stopwatch complex, leading to p53 degradation and sustained proliferation. Loss of GMCL1 stabilizes mitotic 53BP1 levels and restores paclitaxel sensitivity. Our results indicate that combining GMCL1 inhibition with taxane treatment represent a novel strategy to restore taxane sensitivity in cancers. The mass spectrometric data files for the protein complex analysis of FLAG-tagged: (i) wild-type GMCL1 (GMCL1 WT), (ii) a GMCL1 E142K mutant (GMCL1 EK for short), which disrupts its ability to bind with CUL3, and (iii) a GMCL1 BTB/BACK-only mutant, which misses GMCL1's putative C-terminal substrate-binding domain are included in this entry.

2025-03-04 | MSV000097235 | MassIVE

Next Generation Sequencing Analysis of Wild Type and 53BP1-/- Transcriptomes in B lymphocytes

Project description:Absence of 53BP1 influences the profile of DNA rearrangements in B lymphocytes.To determine whether the differences in translocation partner choice were due to differences in transcription, we compared the transcriptome of 53BP1 deficient and wild-type B cells by RNA-Seq and Polymerase II chromatin immunoprecipitation sequencing (ChIP-Seq). Analysis of total mRNA and PolII loading in the presence or absence of 53BP1 in activated B lymphocytes

2013-02-12 | E-GEOD-42350 | biostudies-arrayexpress

A damage independent role for 53BP1 that impacts break order and Igh architecture during CSR

Project description:During Class Switch Recombination (CSR) B cells replace the Igh Cμ/δ exons with another downstream constant region exon (CH), altering the antibody isotype. CSR occurs through the introduction of AID-mediated double strand break (DSBs) in switch regions and subsequent ligation of broken ends. Here we developed an assay to investigate the dynamics of DSB introduction in individual cells. We demonstrate that the upstream switch region Sμ is always targeted first during recombination and that the mechanism underlying this control relies on 53BP1. Surprisingly, regulation of break order occurs through residual binding of 53BP1 to chromatin before the introduction of damage and independent of its established role in DNA repair. Using chromosome conformation capture we show that 53BP1 mediates changes in chromatin architecture that affect break order. Finally, our results explain how changes in Igh architecture in the absence of 53BP1 could promote inversional rearrangements that compromise CSR.

2016-06-16 | GSE81180 | GEO

Transcription profiling of mouseB-cell lymphomas with defined genetic alterations in p53 or p73

Project description:Induction of apoptosis by the tumor suppressor p53 is known to protect from Myc-driven lymphomagenesis. The p53 family member p73 is also a pro-apoptotic protein, which is activated in response to oncogenes like Myc. We therefore investigated whether p73 provides a similar protection from Myc-driven lymphomas as p53. To generate B-cell lymphomas with defined genetic alterations in p53 or p73, we crossed the Eµ-Myc transgenic to mice heterozygous for germ-line deletions in p53 (p53+/) or p73 (p73+/-). Lymphomas which have spontaneously developed in Eµ-Myc transgenic animals with the genotypes p53+/+, p53+/-, p73+/+, p73+/- or p73-/- were isolated when the animals were moribund and further processed for gene expression profiling with 22.5K cDNA microarrays.

2008-12-05 | E-MEXP-1620 | biostudies-arrayexpress

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