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Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program.

ABSTRACT: Although TP53 is the most commonly mutated gene in human cancers, the p53-dependent transcriptional programs mediating tumor suppression remain incompletely understood. Here, to uncover critical components downstream of p53 in tumor suppression, we perform unbiased RNAi and CRISPR-Cas9-based genetic screens in vivo. These screens converge upon the p53-inducible gene Zmat3, encoding an RNA-binding protein, and we demonstrate that ZMAT3 is an important tumor suppressor downstream of p53 in mouse Kras^G12D-driven lung and liver cancers and human carcinomas. Integrative analysis of the ZMAT3 RNA-binding landscape and transcriptomic profiling reveals that ZMAT3 directly modulates exon inclusion in transcripts encoding proteins of diverse functions, including the p53 inhibitors MDM4 and MDM2, splicing regulators, and components of varied cellular processes. Interestingly, these exons are enriched in NMD signals, and, accordingly, ZMAT3 broadly affects target transcript stability. Collectively, these studies reveal ZMAT3 as a novel RNA-splicing and homeostasis regulator and a key component of p53-mediated tumor suppression.

SUBMITTER: Bieging-Rolett KT

PROVIDER: S-EPMC7654708 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The p53-induced RNA-binding protein ZMAT3 is a splicing regulator that inhibits the splicing of oncogenic CD44 variants in colorectal carcinoma.

Project description:p53 is an intensely studied tumor-suppressive transcription factor. Recent studies suggest that the RNA-binding protein (RBP) ZMAT3 is important in mediating the tumor-suppressive effects of p53. Here, we globally identify ZMAT3-regulated RNAs and their binding sites at nucleotide resolution in intact colorectal cancer (CRC) cells. ZMAT3 binds to thousands of mRNA precursors, mainly at intronic uridine-rich sequences and affects their splicing. The strongest alternatively spliced ZMAT3 target was CD44, a cell adhesion gene and stem cell marker that controls tumorigenesis. Silencing ZMAT3 increased inclusion of CD44 variant exons, resulting in significant up-regulation of oncogenic CD44 isoforms (CD44v) and increased CRC cell growth that was rescued by concurrent knockdown of CD44v Silencing p53 phenocopied the loss of ZMAT3 with respect to CD44 alternative splicing, suggesting that ZMAT3-mediated regulation of CD44 splicing is vital for p53 function. Collectively, our findings uncover a p53-ZMAT3-CD44 axis in growth suppression in CRC cells.

| S-EPMC7778265 | biostudies-literature

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-12-18 | GSE150718 | GEO

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_ZMAT3]

Project description:Purpose: p53 is a well-studied protein in which the activation of its main targets is not enough to explain its tumor suppressor effect. Aiming to search for direct p53 targets that mediate less studied processes within p53 pathway, like post-transcriptional regulation, we selected ZMAT3 as the RNA-binding protein most upregulated by p53 activation. Methods: We investigated ZMAT3 targets by using PAR-CLIP and RNA-seq in colorectal cancer cell line HCT116. Results.txt: We found that ZMAT3 binds to ~5000 genes mainly in their introns. It also causes alternative splicing and CD44 was its mostly altered target. ZMAT3 knock-down increased CD44v2-v10 and CD44v3-v10, but decreased CD44s expression. Increased survival and clonogenicity was observed upon knock-down of ZMAT3, which was rescued upon concurrent knock-down of CD44v Conclusions: We propose that ZMAT3 regulates splicing of CD44 following activation by p53, which upregulates CD44s at the expense of CD44v isoforms and leads to a decrease tumorigenicity.

2020-12-18 | GSE150717 | GEO

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [PAR-CLIP_ZMAT3]

Project description:Purpose: p53 is a well-studied protein in which the activation of its main targets is not enough to explain its tumor suppressor effect. Aiming to search for direct p53 targets that mediate less studied processes within p53 pathway, like post-transcriptional regulation, we selected ZMAT3 as the RNA-binding protein most upregulated by p53 activation. Methods: We investigated ZMAT3 targets by using PAR-CLIP and RNA-seq in colorectal cancer cell line HCT116. Results: We found that ZMAT3 binds to ~5000 genes mainly in their introns. It also causes alternative splicing and CD44 was its mostly altered target. ZMAT3 knock-down increased CD44v2-v10 and CD44v3-v10, but decreased CD44s expression. Increased survival and clonogenicity was observed upon knock-down of ZMAT3, which was rescued upon concurrent knock-down of CD44v Conclusions: We propose that ZMAT3 regulates splicing of CD44 following activation by p53, which upregulates CD44s at the expense of CD44v isoforms and leads to a decrease tumorigenicity.

2020-12-18 | GSE150715 | GEO

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_UPF1]

2020-12-18 | GSE150716 | GEO

An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.

Project description:TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors.SignificanceWe analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy. See related commentary by Bhatta and Cooks, p. 1518. This article is highlighted in the In This Issue feature, p. 1501.

| S-EPMC10326602 | biostudies-literature

Non-cell-autonomous tumor suppression by p53.

Project description:The p53 tumor suppressor can restrict malignant transformation by triggering cell-autonomous programs of cell-cycle arrest or apoptosis. p53 also promotes cellular senescence, a tumor-suppressive program that involves stable cell-cycle arrest and secretion of factors that modify the tissue microenvironment. In the presence of chronic liver damage, we show that ablation of a p53-dependent senescence program in hepatic stellate cells increases liver fibrosis and cirrhosis associated with reduced survival and enhances the transformation of adjacent epithelial cells into hepatocellular carcinoma. p53-expressing senescent stellate cells release factors that skew macrophage polarization toward a tumor-inhibiting M1-state capable of attacking senescent cells in culture, whereas proliferating p53-deficient stellate cells secrete factors that stimulate polarization of macrophages into a tumor-promoting M2-state and enhance the proliferation of premalignant cells. Hence, p53 can act non-cell autonomously to suppress tumorigenesis by promoting an antitumor microenvironment, in part, through secreted factors that modulate macrophage function.

| S-EPMC3702034 | biostudies-literature

The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation.

Project description:We show that the splicing regulator PTBP2 controls a genetic program essential for neuronal maturation. Depletion of PTBP2 in developing mouse cortex leads to degeneration of these tissues over the first three postnatal weeks, a time when the normal cortex expands and develops mature circuits. Cultured Ptbp2(-/-) neurons exhibit the same initial viability as wild type, with proper neurite outgrowth and marker expression. However, these mutant cells subsequently fail to mature and die after a week in culture. Transcriptome-wide analyses identify many exons that share a pattern of mis-regulation in the mutant brains, where isoforms normally found in adults are precociously expressed in the developing embryo. These transcripts encode proteins affecting neurite growth, pre- and post-synaptic assembly, and synaptic transmission. Our results define a new genetic regulatory program, where PTBP2 acts to temporarily repress expression of adult protein isoforms until the final maturation of the neuron. DOI: http://dx.doi.org/10.7554/eLife.01201.001.

| S-EPMC3896118 | biostudies-literature

A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas.

Project description:Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs.

| S-EPMC4733364 | biostudies-literature

Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses.

Project description:The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Interestingly, we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53, the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53-induced autophagy does not affect cell cycle arrest in response to DNA damage, it is important for both robust p53-dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together, our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53-dependent apoptosis and cancer suppression.

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