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P53-dependent regulation of gene expression following DNA damage

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE42368 | GEO | 2012/11/20

SECONDARY ACCESSION(S): PRJNA181197

REPOSITORIES: GEO

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p53-dependent regulation of gene expression following DNA damage

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

ATAC-Seq on DNA damaged human fibroblasts

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A p53-topoisome replaces the acutely genotoxic MYC- topoisome to empower DNA-damage repair in cells

Project description:Hyperproliferation driven by the protooncogene MYC has been presumed to elicit a chain of event that leads to DNA damage and activates the tumor suppressor p53 response. This DNA damage has been presumed to derive from hypertranscription and overreplication. Here, we report that MYC-topoisome (MYC/Topoisomerase 1/Topoisomerase 2) formation is genotoxic within minutes of its formation. Topoisome mediated damage activates pATM and p53, that in turn shuts off MYC and dissociates the topoisome in vitro and in vivo. To manage topological and torsional stress generated at its targets, p53 assembles its own topoisome. Because topoisomerase activity is intrinsically DNA-damaging, the p53-topoisome creates initial burst of DNA damage but, because p53 (unlike MYC) upregulates the DNA damage response and activates TDP1 and TDP2, this damage is quickly suppressed. The novel coupling of TOP1 and TOP2 sponsored by p53, creates a tool to support the expression of p53 targets while braking MYC-accelerated cell growth.

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Project description:Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named PINCR (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a critical prosurvival function in colorectal cancer cells (CRC) in vitro and tumor growth in vivo. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including BTG2, RRM2B and GPX1. Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR, we show that PINCR associates with the promoters of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. Our findings uncover a critical prosurvival function of a p53/PINCR/Matrin 3 axis in response to DNA damage in CRC cells.

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Chromatin organization drives the exploration strategy of nuclear factors

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Project description:We report the application of high-throughput sequencing to performed the p53 regulated trancriptome in HCT116 colon cancer cells treated with the DNA damage 5FU. To study the direct targets of p53 we performed ChIP-seq to deterrmined the p53 biding sites and associated with the expression levels. With this study we identified the new genomic regions regulated by p53 and with special attention in those regions that are significally expressed by DNA damage and and are non- coding. HCT116 p53 wt cell transfected with the ASO-SC, ASO lncRNA-1 and ASO unassigned-1 for depletion of this new lncRNAs and treated with the DNA damage drug 5FU for 12h were analyzed in the affimetrix platform HTA2.

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Iwamoto2010 - Cell cycle reponse to DNA damage

Project description:After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.

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