DAZAP2 controls cancer cell chemosensitivity by orchestrating the p53 response upon DNA damage
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ABSTRACT:
PROVIDER: PRJNA645200 | ENA |
REPOSITORIES: ENA
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Project description:The tumor suppressors p53 and HIPK2 play a central role in cell fate decision-making upon DNA damage and regulate cancer cell chemosensitivity. Here we identify the adaptor protein Deleted in Azoospermia-associated protein 2 (DAZAP2) as a novel player in the DNA damage-induced p53 response. Knock-down or genetic deletion of DAZAP2 potentiates cancer cell chemosensitivity in vitro and in vivo. In unstressed cells, DAZAP2 stimulates HIPK2 ubiquitination and degradation through interaction with HIPK2 and the ubiquitin ligase SIAH1. After chemotherapeutic drug-induced DNA damage, DAZAP2 accumulates in the cell nucleus, which is regulated through site-specific phosphorylation by HIPK2. Nuclear DAZAP2 interacts with p53 response elements and specifies p53 target gene expression by modulating a select subset of p53 target genes. Mechanistically, DAZAP2 forms a complex with p53 and modulates target gene expression in association with HDAC1. Our findings identify DAZAP2 as a novel regulator of the p53 response and cancer cell chemosensitivity.
2021-02-10 | GSE154146 | GEO
Project description:Long noncoding RNAs (lncRNAs) are prevalent genes with frequently exquisite regulation but mostly unknown functions. Here we demonstrate a role of lncRNAs in guiding signal transduction. DNA damage activates transcription of DINO (Damage Induced NOncoding) via p53. DINO knockdown blocks DNA damage-induced gene expression and cell cycle arrest. Conversely, enforced expression of DINO activates damage signaling without DNA damage. DINO binds p53 and selectively promotes SET7 methylation of p53 at lysine 372 over other substrates, which stabilizes p53 in an auto-amplification loop. Our results suggest that inducible lncRNA can achieve catalysis-like effects to rewire cellular signaling networks. RNA was isolated from human fetal lung fibroblasts, HCT116 p53+/+, or HCT116 p53-/- cells treated with doxorubicin or sham for 26 hours. Human fetal lung fibroblasts were transfected with siRNAs targeting DINO or non-targeting control and subsequently treated with doxorubicin for 26 hours.
2012-11-20 | E-GEOD-42368 | biostudies-arrayexpress
Project description:Long noncoding RNAs (lncRNAs) are prevalent genes with frequently exquisite regulation but mostly unknown functions. Here we demonstrate a role of lncRNAs in guiding signal transduction. DNA damage activates transcription of DINO (Damage Induced NOncoding) via p53. DINO knockdown blocks DNA damage-induced gene expression and cell cycle arrest. Conversely, enforced expression of DINO activates damage signaling without DNA damage. DINO binds p53 and selectively promotes SET7 methylation of p53 at lysine 372 over other substrates, which stabilizes p53 in an auto-amplification loop. Our results suggest that inducible lncRNA can achieve catalysis-like effects to rewire cellular signaling networks.
2012-11-20 | GSE42368 | GEO
Project description:The control of p53 protein stability is critical to its tumor suppressor functions. The CREB Binding Protein (CBP) transcriptional coactivator co-operates with MDM2 to maintain normally low physiologic p53 levels in cells via an exclusively cytoplasmic ‘E4’ polyubiquitination activity. Utilizing mass spectrometry to identify nuclear and cytoplasmic CBP interacting proteins that regulate compartmentalized CBP E4 activity, we identified Deleted in Breast Cancer 1 (DBC1) as a stoichiometric CBP-interacting protein that negatively regulates CBP–dependent p53 polyubiquitination, stabilizes p53, and augments p53-dependent apoptosis. TCGA analysis demonstrated that solid tumors often retain wild type p53 alleles in conjunction with DBC1 loss, supporting the hypothesis that DBC1 is selected for disruption during carcinogenesis as a surrogate for p53 functional loss. As DBC1 maintains p53 stability in the nucleus where p53 exerts its tumor suppressive transcriptional function, replacement of DBC1 functionality in DBC1-deleted tumors might also enhance p53 function and chemosensitivity for therapeutic benefit.
2019-11-13 | PXD012673 | Pride
Project description:DNA-targeting drugs may damage DNA or chromatin. Many anti-cancer drugs do both, making difficult understanding their mechanism of actions. Using molecules causing DNA breaks without altering nucleosome structure (bleomycin) or destabilizing nucleosomes without damaging DNA (curaxin), we investigated consequences of DNA or chromatin damage in normal and tumor cells. As expected, DNA damage caused p53-dependent growth arrest followed by senescence. Chromatin damage caused higher p53 accumulation than DNA damage, but growth arrest was p53-independent and did not result in senescence. Chromatin damage activated transcription of multiple genes, including classical p53 targets, in a p53-independent manner. These activated genes, though they were not highly expressed, have chromatin organization around transcription start sites (TSS) characteristic for the most highly expressed genes and the highest level of paused RNA polymerase. We proposed that nucleosomes around TSS of these genes are the most sensitive to chromatin damage, and therefore nucleosome loss upon curaxin treatment enables transcription without assistance of sequence-specific transcriptional factors. We confirmed this by showing greater loss of nucleosomes around TSS of these genes upon curaxin treatment and activation of specific p53 reporter in p53-null cells by chromatin damaging agents, but not DNA damaging agents.
2023-09-18 | GSE223327 | GEO
Project description:Telomeres and tumor suppressor protein TP53 (p53) function in genome protection, but a direct role of p53 at telomeres has not yet been described. Here, we have identified non-canonical p53 binding sites within the human subtelomeres that suppress the accumulation of DNA damage at telomeric repeat DNA. These non-canonical subtelomeric p53 binding sites conferred transcription enhancer-like functions that include an increase in local histone H3K9 and H3K27 acetylation and stimulation of subtelomeric transcripts, including telomere-repeat containing RNA (TERRA). p53 suppressed formation of telomere-associated γH2AX and prevented telomere DNA degradation in response to DNA damage stress. Our findings indicate that p53 provides a direct chromatin-associated protection to human telomeres, as well as other fragile genomic sites. We propose that p53-associated chromatin modifications enhance local DNA repair or protection to provide a previously unrecognized tumor suppressor function of p53. p53 binding was analyzed by ChIP-Seq in HCT116 cells treated with camptothecin or untreated control.
2016-01-07 | E-GEOD-75528 | biostudies-arrayexpress
Project description:P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.
| MSV000090292 | MassIVE
Project description:The tumor suppressor p53 is a well-characterized transcription factor that can bind gene promoters and regulate target gene transcription in response to DNA damage. Recent studies, however, have revealed that p53 binding events occur predominantly within regulatory enhancer elements. The effect of p53 binding on enhancer function has not been systematically evaluated. Here, we perform a genome-scale analysis of enhancer activity from p53-bound sequences using a series of massively parallel reporter assays (MPRAs) coupled with the assay for transpose-accessible chromatin (ATAC-Seq). We find that the majority of p53 bound sequences examined are potent regulators of enhancer activity during the DNA damage response. Enhancer regulation requires the presence of the p53 consensus sequence and results in significant induction of target gene transcription. Surprisingly, our analyses revealed that most p53-bound enhancers are located within regions of inaccessible chromatin. Many of these enhancers display significantly increased accessibility in response to DNA damage suggesting that p53 regulates their activity, in part, by altering local chromatin environments. The recognition and activation of inaccessible enhancers may contribute to the ability of the p53 network to function across the diverse chromatin landscapes of different cell and tissue types.
2017-07-21 | GSE83780 | GEO
Project description:Tumor suppressor p53 promotes differentiation of human embryonic stem cells (hESCs), but an in-depth understanding of mechanism is lacking. Here, we define p53 functions in hESCs by genome wide profiling of p53 chromatin interactions and intersection with gene expression during early differentiation and in response to DNA damage. During differentiation, p53 targets and regulates a unique collection of genes, many of which encode transcription factors and developmental regulators with chromatin structure poised by OCT4 and NANOG and marked by repressive H3K27me3 in pluripotent hESCs. In contrast, genes associated with cell migration and motility are bound by p53 specifically after DNA damage. Surveillance functions of p53 in regulation of cell death and cell cycle genes are conserved during both DNA damage and differentiation. Our findings expand the registry of p53 -regulated genes in hESCs and define specific functions of p53 in opposing pluripotency, which are highly distinct from stress-induced p53 response in stem cells. Identification of p53 binding sites in hESC under three conditions: Pluripotent, DNA damaged, Differentiating
2013-10-18 | E-GEOD-39762 | biostudies-arrayexpress
Project description:Tumor suppressor p53 promotes differentiation of human embryonic stem cells (hESCs), but an in-depth understanding of mechanism is lacking. Here, we define p53 functions in hESCs by genome wide profiling of p53 chromatin interactions and intersection with gene expression during early differentiation and in response to DNA damage. During differentiation, p53 targets and regulates a unique collection of genes, many of which encode transcription factors and developmental regulators with chromatin structure poised by OCT4 and NANOG and marked by repressive H3K27me3 in pluripotent hESCs. In contrast, genes associated with cell migration and motility are bound by p53 specifically after DNA damage. Surveillance functions of p53 in regulation of cell death and cell cycle genes are conserved during both DNA damage and differentiation. Our findings expand the registry of p53 -regulated genes in hESCs and define specific functions of p53 in opposing pluripotency, which are highly distinct from stress-induced p53 response in stem cells. Identification of p53 binding sites in hESC under three conditions : Pluripotent, DNA damaged, Differentiating
2013-10-18 | E-GEOD-39912 | biostudies-arrayexpress