Identification of a new ADAR1-dependent RNA editing event in the cyclin dependent kinase CDK13 that promotes thyroid cancer cell hallmarks
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ABSTRACT:
PROVIDER: PRJNA693861 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13500339_1.fastq.gz | Fastqsanger.gz | |||
| SRR13500339_2.fastq.gz | Fastqsanger.gz | |||
| SRR13500340_1.fastq.gz | Fastqsanger.gz | |||
| SRR13500340_2.fastq.gz | Fastqsanger.gz | |||
| SRR13500341_1.fastq.gz | Fastqsanger.gz |
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Project description:Adenosine deaminases acting on RNA (ADAR) catalyze the conversion of adenosines into inosines (A-to-I), modifying a large proportion of cellular RNAs and associated with diverse cancers. We reported previously that ADAR1 is functionally important for thyroid cancer progression and A-to-I editing events are elevated in these tumors. However, the downstream effectors regulated or edited by ADAR1 and the significance of ADAR1 dysregulation in thyroid cancer remain unclear. Here we provide insight, by whole transcriptome sequencing, into the consequences of ADAR1 dysregulation on global gene expression, RNA splicing and RNA editing. Furthermore, we describe for the first time an oncogenic function for CDK13 in thyroid cancer and identified a new ADAR1-dependent RNA editing event that occurs in the coding region of its transcript. Moreover, CDK13 was significantly over-edited in tumor samples and our functional analysis revealed the importance of this specific editing event in promoting cancer cell hallmarks. Finally, we showed that the editing of CDK13 modifies its subcellular localization and that this event could explain, at least in part, the global change in splicing produced by ADAR1 dysregulation. In summary, our data reinforces A-to-I editing as an important pathway in cancer progression, identifying novel mechanisms that open new insights into future treatments in thyroid and other cancer types.
2021-09-15 | GSE165282 | GEO
Project description:BackgroundAdenosine deaminases acting on RNA (ADARs) modify many cellular RNAs by catalyzing the conversion of adenosine to inosine (A-to-I), and their deregulation is associated with several cancers. We recently showed that A-to-I editing is elevated in thyroid tumors and that ADAR1 is functionally important for thyroid cancer cell progression. The downstream effectors regulated or edited by ADAR1 and the significance of ADAR1 deregulation in thyroid cancer remain, however, poorly defined.MethodsWe performed whole transcriptome sequencing to determine the consequences of ADAR1 deregulation for global gene expression, RNA splicing and editing. The effects of gene silencing or RNA editing were investigated by analyzing cell viability, proliferation, invasion and subnuclear localization, and by protein and gene expression analysis.ResultsWe report an oncogenic function for CDK13 in thyroid cancer and identify a new ADAR1-dependent RNA editing event that occurs in the coding region of its transcript. CDK13 was significantly over-edited (c.308A > G) in tumor samples and functional analysis revealed that this editing event promoted cancer cell hallmarks. Finally, we show that CDK13 editing increases the nucleolar abundance of the protein, and that this event might explain, at least partly, the global change in splicing produced by ADAR1 deregulation.ConclusionsOverall, our data support A-to-I editing as an important pathway in cancer progression and highlight novel mechanisms that might be used therapeutically in thyroid and other cancers.
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Project description:ADAR1 mutation causes ZBP1-dependent immunopathology
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Project description:The RNA editing enzyme ADAR1 is essential for suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species. A point mutation in the Z-nucleic-acid binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease. ZBP1 is the only other ZBD-containing mammalian protein and its activation can trigger both cell death and transcriptional responses via the kinases RIPK1 and RIPK3, and the protease caspase-8. Here, we show that the pathology caused by ADAR1 ZBD mutation is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 mutation, without reversing the underlying inflammatory program caused by this mutation. While loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase-8 and RIPK3, or of caspase-8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 mutation. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signaling underlies the autoinflammatory pathology caused by mutation of ADAR1.
2022-06-11 | GSE200854 | GEO
Project description:The RNA editing enzyme ADAR1 is essential for suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species. A point mutation in the Z-nucleic-acid binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease. ZBP1 is the only other ZBD-containing mammalian protein and its activation can trigger both cell death and transcriptional responses via the kinases RIPK1 and RIPK3, and the protease caspase-8. Here, we show that the pathology caused by ADAR1 ZBD mutation is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 mutation, without reversing the underlying inflammatory program caused by this mutation. While loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase-8 and RIPK3, or of caspase-8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 mutation. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signaling underlies the autoinflammatory pathology caused by mutation of ADAR1.
2022-08-10 | GSE200986 | GEO
Project description:The RNA editing enzyme ADAR1 is essential for suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species. A point mutation in the Z-nucleic-acid binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease. ZBP1 is the only other ZBD-containing mammalian protein and its activation can trigger both cell death and transcriptional responses via the kinases RIPK1 and RIPK3, and the protease caspase-8. Here, we show that the pathology caused by ADAR1 ZBD mutation is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 mutation, without reversing the underlying inflammatory program caused by this mutation. While loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase-8 and RIPK3, or of caspase-8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 mutation. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signaling underlies the autoinflammatory pathology caused by mutation of ADAR1.
2022-08-10 | GSE200985 | GEO
Project description:ADAR1 mutation causes ZBP1-dependent immunopathology II
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Project description:ADAR1 mutation causes ZBP1-dependent immunopathology I
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Project description:RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We find disrupted nuclear RNA surveillance is oncogenic. Cyclin Dependent Kinase 13 (CDK13) is mutated in melanoma and patient-mutated CDK13 accelerates zebrafish melanoma. CDK13 mutation causes aberrant RNA stabilization. CDK13 is required for ZC3H14 phosphorylation, which is necessary and sufficient to promote nuclear RNA degradation. Mutant CDK13 fails to activate nuclear RNA surveillance, causing aberrant protein-coding transcripts to be stabilized and translated. Forced aberrant RNA expression accelerates melanoma in zebrafish. We find recurrent mutations in genes encoding nuclear RNA surveillance components in many malignancies, establishing nuclear RNA surveillance as a tumor-suppressive pathway. Activating nuclear RNA surveillance is crucial to avoid accumulation of aberrant RNAs and their ensuing consequences in development and disease.
2023-04-21 | GSE131334 | GEO
Project description:Cyclin-dependent kinases 13 (CDK13) has been suggested to phosphorylate RNA polymerase II and is involved in transcriptional activation. However, whether CDK13 catalyzes other protein substrates and how CDK13 contributes to tumorigenesis remain largely unclear. Herein, we identify key translation machinery components 4E-BP1 and eIF4B as novel CDK13 substrates. CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422 such that genetic or pharmacological inhibition of CDK13 perturbs RNA translation. Polysome profiling analysis shows that MYC oncoprotein synthesis depends on the CDK13-regulated translation in colorectal cancer (CRC), and CDK13 is required for CRC cell proliferation. As mTORC1 has been shown to phosphorylate the 4E-BP1 and eIF4B, knockdown or inhibition of CDK13 in combination with mTORC1 inhibitor rapamycin further dephosphorylates 4E-BP1 and eIF4B and blocks protein synthesis. As a result, dual inhibition of CDK13 and mTORC1 accelerated CRC cell death and again MYC were significantly downregulated upon combination treatment. These findings demonstrate a pro-tumorigenic role of CDK13 in CRC and shed light on the role of CDK13 in protein synthesis by direct phosphorylation of translation initiation factors. Therefore, therapeutic targeting of CDK13 alone or in combination with rapamycin may pave a new way for CRC treatment.
2023-03-09 | GSE224287 | GEO