Endogenous p53 Inhibitor TIRR Dissociates Systemic Metabolic Health from Oncogenic Activity - RNAseq data
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA868216 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21002500.fastq.gz | Fastqsanger.gz | |||
| SRR21002501.fastq.gz | Fastqsanger.gz | |||
| SRR21002502.fastq.gz | Fastqsanger.gz | |||
| SRR21002503.fastq.gz | Fastqsanger.gz | |||
| SRR21002504.fastq.gz | Fastqsanger.gz |
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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: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.
| S-EPMC11325268 | biostudies-literature
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.
2024-07-18 | GSE248032 | GEO
Project description:RQT complex dissociates ribosomes collided on endogenous RQC substrate SDD1
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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:Ribosome-associated quality control (RQC) represents a rescue pathway in eukaryotic cells triggered upon translational stalling. Collided ribosomes are recognized for subsequent dissociation followed by degradation of nascent peptides. However, endogenous RQC-inducing sequences and the mechanism underlying the ubiquitin-dependent ribosome dissociation remain poorly understood. Here, we identified the SDD1 mRNA from S. cerevisiae as an endogenous RQC substrate and reveal its mRNA and nascent peptide dependent stalling mechanism by mutational and cryo-EM analyses. In vitro translation of SDD1 mRNA enabled the reconstitution of Hel2-dependent poly-ubiquitination of collided di- and preferentially tri-ribosomes. Distinct trisome architecture was visualized by cryo-EM and provides the structural basis for more efficient recognition by Hel2 over disomes. Subsequently, the Slh1 helicase subunit of the RQC trigger (RQT) complex preferentially dissociates the first stalled poly-ubiquitinated ribosome in an ATP-dependent manner. Together, these findings provide fundamental mechanistic insights into RQC and its physiological role in maintaining cellular protein homeostasis.
2020-01-27 | GSE131214 | GEO
Project description:53BP1 influences genome stability via two independent mechanisms: (1) regulating DNA double-strand break (DSB) repair and (2) enhancing p53 activity. We discovered a protein, Tudor-interacting repair regulator (TIRR), that associates with the 53BP1 Tudor domain and prevents its recruitment to DSBs. Here, we elucidate how TIRR affects 53BP1 function beyond its recruitment to DSBs and biochemically links the two distinct roles of 53BP1. Loss of TIRR causes an aberrant increase in the gene transactivation function of p53, affecting several p53-mediated cell-fate programs. TIRR inhibits the complex formation between the Tudor domain of 53BP1 and a dimethylated form of p53 (K382me2) that is poised for transcriptional activation of its target genes. TIRR mRNA expression levels negatively correlate with the expression of key p53 target genes in breast and prostate cancers. Further, TIRR loss is selectively not tolerated in p53-proficient tumors. Therefore, we establish that TIRR is an important inhibitor of the 53BP1-p53 complex.
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Project description:NEAT1 Modulates the TIRR/53BP1 Complex to Maintain Genome Integrity
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Project description:Identification of TIRR ubiquitination site in 293T cells by mass spec
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