NEAT1 Modulates the TIRR/53BP1 Complex to Maintain Genome Integrity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1155690 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30544927.fastq.gz | Fastqsanger.gz | |||
| SRR30544928.fastq.gz | Fastqsanger.gz | |||
| SRR30511939.fastq.gz | Fastqsanger.gz | |||
| SRR30511940.fastq.gz | Fastqsanger.gz | |||
| SRR30511941.fastq.gz | Fastqsanger.gz |
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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
Project description:Tudor interacting repair regulator (TIRR) is a well-studied p53 binding protein 1 (53BP1) interactor in response to DNA double strand breaks (DSBs). TIRR is also an RNA binding protein, however its role in RNA regulation in response to cellular insults is not understood. Here we show that TIRR binds to specific group of mRNAs in response to DNA damage. TIRR bound transcripts encode for transcription factors and RNA polymerase II (RNAPII) transcription regulators. Furthermore, TIRR modulates the formation of RNA processing bodies (P bodies/PBs), in response to DSBs. TIRR also regulates the formation of the closely related but distinct compartments known as stress granules (SGs) in response to cell stress. Furthermore, TIRR dissociates from 53BP1 in response to sodium arsenite treatment independently of Ataxia Telangiectasia Mutated Protein (ATM) signalling. Finally, TIRR interacts with the nuclear export protein Exportin-1 (XPO1) upon DNA damage. TIRR bound RNA co-localises with PB and SGs and TIRR depletion leads to nuclear RNA retention. This work reveals that TIRR orchestrates mRNA nuclear export, metabolism and storage in PBs/SGs. Hence TIRR regulates RNA mediated DNA damage and cell stress responses independently of its canonical 53BP1 binding role.
2024-07-18 | GSE227684 | GEO
Project description:Tudor interacting repair regulator (TIRR) is a well-studied p53 binding protein 1 (53BP1) interactor in response to DNA double strand breaks (DSBs). TIRR is also an RNA binding protein, however its role in RNA regulation in response to cellular insults is not understood. Here we show that TIRR binds to specific group of mRNAs in response to DNA damage. TIRR bound transcripts encode for transcription factors and RNA polymerase II (RNAPII) transcription regulators. Furthermore, TIRR modulates the formation of RNA processing bodies (P bodies/PBs), in response to DSBs. TIRR also regulates the formation of the closely related but distinct compartments known as stress granules (SGs) in response to cell stress. Furthermore, TIRR dissociates from 53BP1 in response to sodium arsenite treatment independently of Ataxia Telangiectasia Mutated Protein (ATM) signalling. Finally, TIRR interacts with the nuclear export protein Exportin-1 (XPO1) upon DNA damage. TIRR bound RNA co-localises with PB and SGs and TIRR depletion leads to nuclear RNA retention. This work reveals that TIRR orchestrates mRNA nuclear export, metabolism and storage in PBs/SGs. Hence TIRR regulates RNA mediated DNA damage and cell stress responses independently of its canonical 53BP1 binding role.
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Project description:It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR’s oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.
2024-06-10 | GSE210900 | GEO
Project description:53BP1 is primarily known as a key regulator in DNA double-strand break (DSB) repair. However, the mechanism of DSB-triggered cohesin modification-modulated chromatin structure on the recruitment of 53BP1 remains largely elusive. Here we identified acetyltransferase ESCO2 as a regulator for DSB-induced cohesin-dependent chromatin structure dynamics, which promotes 53BP1 recruitment. Mechanistically, in response to DNA damage, ATM phosphorylates ESCO2 S196 and T233. MDC1 recognizes phosphorylated ESCO2 and recruits ESCO2 to DSB sites. ESCO2-mediated acetylation of SMC3 stabilizes cohesin complex conformation and regulates the chromatin structure at DSB breaks, which is essential for the recruitment of 53BP1 and the formation of 53BP1 microdomains. Furthermore, depletion of ESCO2 in both colorectal cancer cells and xenografted nude mice sensitizes cancer cells to chemotherapeutic drugs. Collectively, our results reveal a molecular mechanism for the ATM-ESCO2-SMC3 axis in DSB repair and genome integrity maintenance with a vital role in chemotherapy response in colorectal cancer.
2023-12-16 | GSE221266 | GEO
Project description:Macrophages Maintain Epithelium Integrity by Limiting Fungal Product Absorption
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Project description:Although thousands of long non-coding RNAs (lncRNAs) are localized in the nucleus, only a few dozen have been functionally characterized. We found that nuclear paraspeckle assembly transcript 1 (NEAT1), an essential lncRNA for the formation of nuclear body paraspeckles, is induced by poly I:C stimulation, resulting in excess formation of paraspeckles. Using microarray analysis, we investigated whether NEAT1 induction followed by excess formation of paraspeckles was involved in poly I:C-inducible gene expression. We want to know the NEAT1-regulated genes. To the end, HeLa TO cells with and without poly I:C stimulation and NEAT1-knock down cells with and without poly I:C stimulation and cells transfected with mock plasmid or Neat1v2 expression plasmid alone were used for RNA extraction and hybridization on Affymetrix microarrays.
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Project description:We investigated the role of NEAT1 knockdown on neuronal excitability in iPSC-derived neurons.
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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
Project description:Long noncoding RNAs (lncRNAs) are important regulators of chromatin; however, the mechanistic roles for many lncRNAs are poorly understood in part because their direct interactions with genomic loci and proteins are difficult to assess. We used CHART-seq to map the genomic binding sites for two highly expressed human lncRNAs, NEAT1 and MALAT1, which localize within the nucleus to paraspeckles and nuclear speckles, respectively. We show that NEAT1 and MALAT1 localize to hundreds of genomic sites in human cells, primarily over active genes. NEAT1 and MALAT1 exhibit colocalization to many of these loci, but display distinct gene body binding patterns at these sites, suggesting independent but complementary functions for these RNAs. Protein mass spectrometry analysis of CHART-enriched material (CHART-MS) identified numerous proteins enriched by both lncRNAs, supporting complementary binding and function, in addition to unique associated proteins. Transcriptional inhibition or stimulation affects the localization of NEAT1 to active chromatin sites, implying that DNA sequence itself does not target NEAT1 to chromatin and that localization responds to cues involved in the transcription process. Paired-end CHART-seq was performed for a single replicate of each capture oligonucleotide in untreated MCF-7 cells to establish binding sites of these RNAs, for a total of 6 samples. To investigate the effects of transcriptional inhibition and E2 stimulation on the localization of these RNAs, we performed paired-end CHART-seq with each capture oligonucleotide for two biological replicates of flavopiridol- and vehicle (DMSO)-treated MCF-7 cells and for two biological replicates of E2- and vehicle (ethanol)-treated MCF-7 cells. To establish the overlap of NEAT1 and MALAT1 binding sites with a known component of paraspeckles (NEAT1-containing subnuclear body), we performed paired-end ChIP-seq for the paraspeckle component PSF in MCF-7 cells, as well as a single-end biological replicate.
2014-08-12 | E-GEOD-58444 | biostudies-arrayexpress